ATF6 Modulators and Uses Thereof

Abstract

Compounds are provided as modulators of activating transcription factor 6 (ATF6). Provided are compounds of formula (I), or pharmaceutically acceptable salts thereof, which may find use as therapeutic agents for the treatment of diseases or disorders mediated by ATF6, and may find particular use in the treatment of viral infections, neurodegenerative diseases, vascular diseases, or cancer. TIFF2026041801000131.tif26161

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 913,126, filed October 9, 2019, the disclosure of which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates generally to therapeutic agents that may be useful as modulators of activating transcription factor 6 (ATF6).

[0003] Submitting a sequence listing as an ASCII text file The contents of the following submitted document, an ASCII text file, are incorporated herein by reference in its entirety: Sequence Listing Computer Readable Form (CRF) (Filename: 196052001440SEQLIST.TXT, Date Recorded: October 8, 2020, Size: 1KB) [Background technology]

[0004] The accumulation of misfolded proteins in the ER of mammalian cells overwhelms the folding machinery, resulting in a stress response. Cells attempt to reduce the ER protein load by activating a vast gene expression program that sends signals from the ER to the nucleus and improves the protein folding capacity of the ER. However, if this system fails and homeostasis cannot be reestablished, cells die by undergoing apoptosis. The Unfolded Protein Response (UPR) is an evolutionarily conserved signaling pathway that maintains protein homeostasis in response to ER stress.

[0005] The UPR consists of three intertwined signaling pathways: (1) PERK (protein kinase RNA-like ER kinase), (2) IRE1 (inositol-requiring enzyme 1α), and (3) ATF6 (activating transcription factor 6) (McKimpson, W.M. et al., Circ Res, 2017, 120(5):759-761). Activation of the ATF6 pathway leads to the upregulation of genes such as BIP (Grp78), CHOP, or XBP-1, which enhance the ability of the endoplasmic reticulum to fold proteins or mediate quality control. ATF6 acts in concert with IRE1, and as one of the target genes of ATF6, XBP1 is a major substrate of IRE1 (Yoshida, H., et al., Cell, 2001, 107(7):881-891). PERK also plays several other roles, including halting the production of new proteins to temporarily reduce the protein folding load.

[0006] ATF6 is a type II transmembrane protein localized in the ER that functions as an ER stress sensor and transcription factor (Adachi, Y., et al., Cell Struct Funct, 2008, 33(1):75-89; Wu, J., et al., Dev Cell, 2007, 13(3):351-64). When demand exceeds the folding capacity of the ER, ATF6 is transported from the ER to the Golgi apparatus, where sequential cleavage by two Golgi-resident proteases, site-1 and site-2 proteases (S1P and S2P), releases its N-terminal domain (ATF6N) from the Golgi membrane, transports it to the nucleus, and activates the transcription of its target genes (Ye, J., et al., Mol Cell, 2000, 6(6):1355-64). This activation involves ATF6 binding to a consensus sequence called the ER stress response element (ERSE). The consensus sequence for ERSE is CCAATCGGCGGCGGCCACG (SEQ ID NO: 1).

[0007] Unlike other arms of the UPR regulated by PERK and IRE1, the ATF6 arm has not been shown to be substantially associated with proapoptotic signaling (Hetz, C. and Papa, FR 2018; Sano, R. and Reed, JC 2013). Instead, ATF6 primarily functions in the so-called "adaptive UPR," which is designed to promote protective adaptive remodeling and recovery of cellular physiology after acute physiological and pathological insults. As part of the adaptive UPR, ATF6 integrates with multiple other stress-responsive signaling pathways to sensitively adapt cellular physiology to various types of ER insults.

[0008] In the context of the UPR, this integration can be achieved through heterodimerization of ATF6 with other UPR-regulated bZIP transcription factors, such as XBP1s (Yamamoto, K. et al. 2007; Shoulders, MD et al. 2013) or ATF6b (Thuerauf, DJ et al. 2007; Thuerauf, DJ et al. 2004; Forouhan, M. et al. 2018; Pieper, LA et al. 2017). ATF6 also has the potential to heterodimerize with other bZIP transcription factors, such as CREB-H, which are similarly regulated through mechanisms involving S1P / S2P-dependent proteolysis (Asada, R. et al. 2011; Zhang, K. et al. 2006). Apart from heterodimerization, ATF6 signaling also integrates with other stress-responsive signaling pathways, interacting with other transcription factors, such as NRF1, PGC1a, PPARa, and ERRg (Chen, X. et al. 2016; Wu, J. et al. 2011; Misra, J. et al. 2013; Baird, L. et al. 2017).

[0009] The ability of ATF6 to integrate with other signaling pathways through multiple mechanisms reflects the unparalleled potential of this UPR signaling arm to orchestrate protective cellular responses against a range of pathological insults that induce ER stress, in addition to ER proteostasis remodeling. Establishing new pharmacological approaches for both inhibiting and activating ATF6 signaling will provide new opportunities to carefully examine the timing and extent of ATF6 signaling involved in protecting different tissues against cancer, autoimmune diseases, neurodegeneration, metabolic diseases, or I / R.

[0010] Several strategies for manipulating the UPR have been utilized to define possible links between ER stress and human disease, with significant progress being made in cancer and neurodegeneration.

[0011] In cancer, tumor growth relies on the UPR as a selective force to drive malignant transformation (Cubillos-Ruiz, JR et al. 2016), in addition to remodeling the tumor microenvironment and anti-cancer immune responses (Song, M and Cubillos-Ruiz, JR 2019) and influencing other central hallmarks of cancer (Urra, H. et al. 2016).

[0012] For example, multiple myeloma (MM) remains a largely incurable malignancy despite high-dose chemotherapy, autologous stem cell transplantation, and novel agents. Proteasome inhibitors (PIs) such as bortezomib have improved the response rate and survival of patients with MM. The overall patient response rate to bortezomib and dexamethasone in newly diagnosed MM is approximately 67%. In relapsed and refractory MM, the response rate decreases to approximately 40–60%. Thus, a significant number of bortezomib-resistant MM patients exist. MM cells are intrinsically sensitive to PIs due to their abundant immunoglobulin production, which requires constant expression of physiological UPR genes. This is thought to lower their threshold for the induction of a proapoptotic / terminal UPR in response to PI-induced endoplasmic reticulum (ER) stress. One hallmark of UPR induction is increased transcription and translation of ER molecular chaperones. These genes are induced by the UPR transcription factors XBP1 and ATF6. Although XBP1 splicing and its resulting activation have been shown to be inhibited in PI-treated MM cells, findings indicate that the high basal expression of two XBP1 target gene products, GRP78 and GRP94, is not reduced by PI treatment. The observation that the XBP1-dependent UPR target gene ERdj4 was normally induced by PI indicates that the UPR remains functional in PI-treated MM cells. Because both XBP1 and ATF6 can bind to ER stress response elements in the promoters of UPR target genes, it has been shown that ATF6 can compensate for the reduced XBP1 activity in PI-treated MM cells. Consistent with this, induction of GRP78 and GRP94 is associated with XBP1. - / -It has been shown that expression of GRP94 is only slightly impaired in B cells, and that it requires either ATF6 or XBP1, but not both. Interestingly, previous studies have shown that XBP1 predicts sensitivity to bortezomib, with its levels proportionally correlated with sensitivity to bortezomib. Recently, Harnoss JM et al. demonstrated, using genetic and pharmacological disruption, in vitro and in vivo, that the IRE1α-XBP1s pathway plays an important role in MM growth. Indeed, inhibition of IRE1α kinase activity using small molecules has been demonstrated to be a potentially effective and safe therapy for clinically treating MM.

[0013] In addition to the amount of ER-resident chaperones, PI sensitivity is also thought to be involved in the effectiveness of immunoglobulin folding in MM cells. High basal expression of the ER-resident chaperones GRP78 and GRP94 in MM cell lines is consistent with reports that physiological UPR gene expression is required for professional secretory cell function. Elevated levels of ER chaperones are characteristic of plasma cells, and their expression is essential for proper antibody assembly and secretion. GRP78 has been shown to stably bind unbound immunoglobulin heavy chains and assist in immunoglobulin assembly. Furthermore, both GRP78 and GRP94 are important for immunoglobulin light chain folding and targeting unassembled subunits for degradation. The fact that GRP78 and GRP94 expression is only slightly increased in MM cells treated with PI and classical ER stress agents indicates that they already express near-maximal levels of cytoprotective UPR proteins to function as secretory cells. Thus, these cells may have a lower threshold (compared to non-secretory cells) for the induction of a terminal UPR after any additional stress on the ER. Thus, more resistant myeloma clones and other non-secretory malignancies may be sensitized to bortezomib by combining them with agents that interfere with the UPR, such as modulators of the ATF6 signaling pathway.

[0014] On the other hand, the protein folding capacity of professional secretory cells is compromised in some diseases, leading to cell degeneration and death through terminal UPR signaling. For example, dysregulation of UPR signaling in insulin-secreting pancreatic β cells leads to premature cell loss, insulin deficiency, and diabetes. Although neurons are not typically considered classical secretory cells, the accumulation of abnormal aggregates can nonetheless induce the terminal UPR in neurons, leading to neurodegeneration (Hetz, C. and Saxena, S. 2017). ER stress has been implicated in eye diseases and in the death of neuronal photoreceptor cells (Kroeger, H. et al. 2019).

[0015] Additionally, many diseases result in circulatory disorders, which can cause ischemic conditions in various organs, including the brain, heart, and kidneys (Benjamin, EJ et al. 2018). In these settings, prolonged ischemia leads to irreversible damage, which can be partially alleviated by clinical interventions that restore blood flow through reperfusion (Hausenloy, DJ and Yellon, DM 2016). While reperfusion is necessary to mitigate ongoing ischemic damage, reperfusion itself is generally known to result in some additional damage as a result of reactive oxygen species (ROS) (Murphy, E. and Steenbergen, C. 2008). The complex nature of cellular injury associated with ischemia or ischemia-followed-reperfusion (I / R) has previously been shown to affect the levels and activity of numerous signaling pathways and transcription factors. One more recently investigated I / R-activated pathway involves disruption of proteostasis. To protect against I / R-induced pathological ER stress, tissues activate endogenous adaptive stress-responsive signaling pathways, such as the unfolded protein response (UPR).

[0016] Recent evidence highlights the protective role of the ATF6 arm of the UPR in mitigating adverse outcomes associated with ischemia / reperfusion (I / R) injury in multiple disease models (Kudo, T. et al. 2008; Oida, Y. et al. 2008; Prachasilchai, W. et al. 2009; Oida, Y. et al. 2010; Blackwood, EA et al. 2019; Yu, Z. et al. 2017; Bi, X. et al. 2018), indicating ATF6 as a potential therapeutic target for pharmacological intervention in diverse ischemia-related disorders together with activator compounds (Plate, L. et al. 2016; Glembotski, CC et al. 2019).

[0017] ATF6-activated transcriptional targets play a role in the pathogenesis and development of various diseases, including viral infections, cancer, neurodegeneration, Alzheimer's disease, cerebral ischemia, hereditary cerebellar atrophy and ataxia, type 2 diabetes, and diabetic nephropathy, as well as cardiovascular diseases such as myocardial atrophy, heart failure, ischemic heart disease, and atherosclerosis (Chu, WS, et al., Diabetes, 2007, 56(3):856-62; Vekich, JA, et al., J Mol Cell Cardiol, 2012, 53(2):259-67; Liu, CL, et al., Int J Mol Med, 2016, 37(2):407-14). Therefore, modulation of ATF6-mediated transcription may provide a therapeutic strategy for these and other diseases involving ATF6 activity. Summary of the Invention

[0018] In one embodiment, a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein A, R 1 , R 2 , R 3 , R 4 , R 5, R 6 , R 7 , R d , and -- are as detailed herein.

[0019] In another aspect, a method for treating a disease or disorder mediated by activating transcription factor 6 (ATF6) in an individual in need thereof is provided, the method comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound. In some embodiments, the disease or disorder mediated by activating transcription factor 6 (ATF6) is a viral infection, cancer, a neurodegenerative disease, or a vascular disease. In certain embodiments, the disease or disorder is a viral infection, hereditary cerebellar atrophy and ataxia, Alzheimer's disease, type 2 diabetes, diabetic nephropathy, myocardial atrophy, heart failure, atherosclerosis, ischemia, ischemic heart disease, or cerebral ischemia. In some embodiments, the disease or disorder characterized by activating transcription factor 6 (ATF6) is cancer. In some embodiments, the ATF6 is ATF6α.

[0020] In another aspect, a method for treating a disease or disorder characterized by activation of transcription factor 6 (ATF6) in an individual in need thereof is provided, the method comprising administering to the individual a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound. In some embodiments, the disease or disorder characterized by activation of ATF6 is a viral infection, cancer, a neurodegenerative disease, or a vascular disease. In certain embodiments, the disease or disorder is a viral infection, hereditary cerebellar atrophy and ataxia, Alzheimer's disease, type 2 diabetes, diabetic nephropathy, myocardial atrophy, heart failure, atherosclerosis, ischemia, ischemic heart disease, or cerebral ischemia. In some embodiments, the disease or disorder characterized by activation of transcription factor 6 (ATF6) is cancer. In some embodiments, the ATF6 is ATF6α.

[0021] In another aspect, there is provided a method of treating cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound.

[0022] In some embodiments, the cancer is breast cancer, colon cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, osteosarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal cancer, or adenocarcinoma. In some embodiments, the one or more cancer cells in the individual are dormant cancer cells.

[0023] In some embodiments, the individual has undergone prior treatment. In some embodiments, the cancer is resistant or refractory to prior treatment. In some embodiments, the cancer is resistant to treatment with a ubiquitin-proteasome pathway inhibitor, a taxane, a Cox-2 inhibitor, a platinum-based anti-cancer drug, an anthracycline, a pyrimidine analog, a topoisomerase inhibitor, an mTOR inhibitor, an immune checkpoint inhibitor, or an agent used in immuno-oncology.

[0024] In some embodiments, the method further comprises administering radiation. In some embodiments, the method further comprises administering a second anti-cancer agent. In some embodiments, the second anti-cancer agent targets an immune checkpoint protein.

[0025] In another aspect, methods are provided for treating angiogenesis-related diseases or disorders in an individual in need thereof, comprising administering to the individual an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound. In some embodiments, the method further comprises administering a second antiangiogenic agent.

[0026] In some embodiments of the methods disclosed herein, the method further comprises administering a second agent that modulates the unfolded protein response or the integrated stress response. In some embodiments, the second agent inhibits the IRE1 / XBP1 pathway.

[0027] In another aspect, a method for modulating (activating or inhibiting) ATF6 in an individual is provided, the method comprising administering to the individual a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound.

[0028] In another aspect, a method for regulating (activating or inhibiting) ATF6 in a cell is provided, comprising delivering to the cell a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound.

[0029] Pharmaceutical compositions are also provided, including (A) a compound described herein, e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and (B) a pharmaceutically acceptable carrier or excipient. Kits are also provided, including a compound described herein, or a salt thereof, and optionally, instructions for use. The compounds described herein, or a pharmaceutically acceptable salt thereof, are also provided for the manufacture of a medicament for the treatment of a disease or disorder characterized by ATF6 activation. In some embodiments, the disease or disorder is cancer, a neurodegenerative disease, or a vascular disease. In certain embodiments, the disease or disorder is a viral infection, hereditary cerebellar atrophy and ataxia, Alzheimer's disease, type 2 diabetes, diabetic nephropathy, myocardial atrophy, heart failure, atherosclerosis, ischemia, ischemic heart disease, or cerebral ischemia. DETAILED DESCRIPTION OF THE INVENTION

[0030] definition As used herein, unless expressly stated otherwise, the use of the terms "a," "an," etc. refers to one or more.

[0031] Reference herein to "about" a value or parameter includes (and describes) embodiments directed to that value or parameter itself. For example, a description that refers to "about X" includes a description of "X."

[0032] As used herein, "alkyl" has the specified number of carbon atoms (i.e., C1-C6), unless otherwise specified. 10 refers to and includes saturated linear (i.e., unbranched) or branched monovalent hydrocarbon chains or combinations thereof, having from 1 to 20 carbon atoms ("C1-C" means 1 to 10 carbon atoms). Particular alkyl groups are those having from 1 to 20 carbon atoms ("C1-C" means 1 to 20 carbon atoms). 20 alkyl), 1 to 10 carbon atoms (C1 to C 10 alkyl), 6 to 10 carbon atoms (C6 to C 10 and those having 1 to 6 carbon atoms ("C1-C6 alkyl"), 2 to 6 carbon atoms ("C2-C6 alkyl"), or 1 to 4 carbon atoms ("C1-C4 alkyl"). Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0033] "Alkoxy" refers to the group RO- where R is alkyl and includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, 1,2-dimethylbutoxy, and the like.

[0034] As used herein, "aryl" or "Ar" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl), which may or may not be aromatic. Particular aryl groups have 6 to 14 ring carbon atoms ("C6-C6"). 14Aryl groups have two or more rings, in which at least one ring is non-aromatic, and may be connected to the parent structure at either an aromatic ring position or a non-aromatic ring position. In one variation, aryl groups have two or more rings, in which at least one ring is non-aromatic, and are connected to the parent structure at an aromatic ring position.

[0035] As used herein, unless otherwise specified, "cycloalkyl" refers to a cycloalkyl group having the specified number of carbon atoms (i.e., C3-C6). 10 "Cycloalkyl" refers to and includes saturated cyclic monovalent hydrocarbon structures ("C-C cycloalkyl" means 3 to 10 carbon atoms). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl. Cycloalkyls containing more than one ring may be fused, spiro, or bridged, or combinations thereof. Particular cycloalkyl groups are those having 3 to 12 ring carbon atoms. Preferred cycloalkyls are cyclic hydrocarbons having 3 to 8 ring carbon atoms ("C-C cycloalkyl"), 3 to 6 carbon atoms ("C-C cycloalkyl"), or 3 to 4 ring carbon atoms ("C-C cycloalkyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0036] "Halo" or "halogen" refers to Group 17 elements having atomic numbers 9-85. Preferred halo groups include fluorine, chlorine, bromine, and iodine radicals. When a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. For example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may be the same halogen, but are not necessarily the same; thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced by a halo group is referred to as a "perhaloalkyl." A preferred perhaloalkyl group is trifluoromethyl (-CF3). Similarly, "perhaloalkoxy" refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon that constitutes the alkyl portion of the alkoxy group. One example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

[0037] The term "haloalkyl" refers to an alkyl group having one or more halo substituents, or one, two, or three halo substituents. Examples of haloalkyl groups include -CF, -(CH)F, -CHF, CHBr, -CHCF, and -CHCHF.

[0038] As used herein, "heteroaryl" refers to an unsaturated aromatic cyclic group having 1 to 14 ring carbon atoms and at least one ring heteroatom, including, but not limited to, nitrogen, oxygen, and sulfur. Heteroaryl groups can have a single ring (e.g., pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl, benzothienyl), which may or may not be aromatic. Particular heteroaryl groups are 5- to 14-membered rings having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; 5- to 10-membered rings having 1 to 8 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 5-, 6-, or 7-membered rings having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, certain heteroaryl groups are monocyclic aromatic 5-, 6-, or 7-membered rings having 1 to 6 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, certain heteroaryl groups are polycyclic aromatic rings having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. Heteroaryl groups having two or more rings, in which at least one ring is non-aromatic, may be connected to the parent structure at either an aromatic ring position or a non-aromatic ring position. In one variation, heteroaryl groups having two or more rings, in which at least one ring is non-aromatic, may be connected to the parent structure at an aromatic ring position. Heteroaryl groups may be connected to the parent structure at a ring carbon atom or a ring heteroatom.

[0039] As used herein, "heterocycle," "heterocyclic," or "heterocyclyl" refers to a saturated or unsaturated non-aromatic cyclic group having a single ring or multiple fused rings and having 1 to 14 ring carbon atoms and 1 to 6 ring heteroatoms, such as nitrogen, sulfur, or oxygen, and the like. Heterocycles containing two or more rings may be fused, bridged, or spiro, or any combination thereof, but exclude heteroaryl groups. Heterocyclyl groups may be optionally and independently substituted with one or more substituents described herein. Particular heterocyclyl groups are 3- to 14-membered rings having 1 to 13 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 12-membered rings having 1 to 11 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 10-membered rings having 1 to 9 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; 3- to 8-membered rings having 1 to 7 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 3- to 6-membered rings having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, heterocyclyl includes a monocyclic 3-, 4-, 5-, 6-, or 7-membered ring having 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 ring carbon atoms and 1 to 2, 1 to 3, or 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, heterocyclyl includes a polycyclic non-aromatic ring having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0040] A "pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0041] As used herein, "treatment" or "treating" refers to an approach to obtaining beneficial or desired results, including clinical results. For example, beneficial or desired results include, but are not limited to, one or more of the following: reducing symptoms caused by a disease, improving the quality of life of an individual suffering from a disease, reducing the dose of other medications needed to treat the disease, slowing the progression of the disease, and / or extending the survival of an individual. With respect to cancer or other unwanted cell proliferation, beneficial or desired results include shrinking a tumor (reducing tumor size), slowing the rate of tumor growth (e.g., suppressing tumor growth), reducing the number of cancer cells, inhibiting, delaying, or slowing to some extent, and preferably stopping, cancer cell invasion into peripheral organs, inhibiting (slowing to some extent, and preferably stopping) tumor metastasis, inhibiting tumor growth, preventing or delaying tumor onset and / or recurrence, and / or alleviating to some extent one or more symptoms associated with cancer. In some embodiments, beneficial or desired results include preventing or delaying recurrence of unwanted cell proliferation, etc.

[0042] As used herein, an "effective dosage" or "effective amount" of a compound or salt thereof or pharmaceutical composition is an amount sufficient to achieve a beneficial or desired result. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk of, reducing the severity of, or delaying the onset of, disease, including the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes exhibited during disease development. For therapeutic use, beneficial or desired results include ameliorating, alleviating, reducing, delaying, or reducing one or more symptoms resulting from the disease, improving the quality of life of a person suffering from the disease, reducing the dose of other pharmaceutical agents required to treat the disease, enhancing the effect of another pharmaceutical agent, such as through targeting, delaying disease progression, and / or prolonging survival. With respect to cancer or other undesired cell proliferation, an effective amount includes an amount sufficient to shrink a tumor and / or reduce the rate of tumor growth (e.g., inhibit tumor growth), or prevent or delay other undesired cell proliferation. In some embodiments, an effective amount is an amount sufficient to delay onset. In some embodiments, an effective amount is an amount sufficient to prevent or delay recurrence. An effective amount can be administered in one or more administrations, and in the case of cancer, an effective amount of a drug or composition can: (i) reduce the number of cancer cells, (ii) reduce tumor size, (iii) inhibit, delay, slow to some extent, or preferably stop cancer cell invasion into peripheral organs, (iv) inhibit (i.e., slow to some extent, or preferably stop) tumor metastasis, (v) inhibit tumor growth, (vi) prevent or delay tumor recurrence, and / or (vii) alleviate to some extent one or more symptoms associated with cancer. An effective dosage can be administered in one or more administrations. For purposes of this disclosure, an effective dosage of a compound or salt thereof, or pharmaceutical composition is an amount sufficient to achieve prophylactic or therapeutic treatment, either directly or indirectly. It is intended and understood that an effective dosage of a compound or salt thereof, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.Thus, an "effective dosage" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if a desired result can or is achieved in conjunction with one or more other agents.

[0043] As used herein, the term "individual" refers to a mammal, including a human. An individual includes, but is not limited to, a human, a cow, a horse, a cat, a dog, a rodent, or a primate. In some embodiments, the individual is a human. The individual (such as a human) may have advanced disease or a less severe disease, e.g., a low tumor burden. In some embodiments, the individual is in an early stage of a proliferative disease (such as cancer). In some embodiments, the individual is in an advanced stage of a proliferative disease (such as advanced cancer).

[0044] It is understood that the embodiments and variations described herein also include "consisting of" and / or "consisting essentially of" embodiments and variations.

[0045] All references to publications, patents, patent applications, and published patent applications are incorporated herein by reference in their entirety. compound

[0046] In one embodiment, a compound of formula (I):

[0047] [ka] or a pharmaceutically acceptable salt thereof (In the formula, R d is H or C1-C6 alkyl, R 1 is C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 haloalkyl; L is -CH2- or absent; -- is a bond or is absent, R 2 , R3 , R 4 , R 5 , and R 6 are each independently H, halo, CN, C-C alkyl, or C-C haloalkyl; R 2 , R 3 , R 4 , R 5 , and R 6 at least two of are halo, CN, C-C alkyl, or C-C haloalkyl, and / or alternatively R 2 , R 3 , R 4 , R 5 , and R 6 One of the is CN or Or R 2 , R 4 , R 5 , and R 6 are each independently H, halo, CN, C-C alkyl, or C-C haloalkyl; -- is a bond, so R 3 But R 1 and together with the atoms to which they are attached form a 5- or 6-membered ring, which 5- or 6-membered ring is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of halo, CN, —OH, C1-C6 alkyl, and C1-C6 haloalkyl; A is,

[0048] [ka] and R a is a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is unsubstituted or substituted with 1 to 4 groups selected from the group consisting of OH, halo, C1-C6 alkyl, and C1-C6 alkoxy; However, A is

[0049] [ka] and Ra is 2-furyl or 2-thiofuryl, at least one of (i.) to (vi.) applies; (i.) L is absent, R 1 is C1-C6 alkyl, (ii.) -- is a bond, whereby R 3 But R 1 and together with the atoms to which they are attached form a 5- or 6-membered carbocyclic ring, provided that when a 5-membered carbocyclic ring is formed, R 2 , R 4 , R 5 , and R 6 at least one of is halo, CN, C1-C6 alkyl, or C1-C6 haloalkyl; (iii.)R 2 , R 3 , R 4 , R 5 , and R 6 One of them is CN, (iv.)R 4 and R 5 are each independently Cl, Br, I, CN, C1-C6 alkyl, or C1-C6 haloalkyl; (v.) R 2 and R 3 are each Cl, (vi.)R 2 , R 3 , R 4 , R 5 , and R 6 at least one of R is F, Br, I, CN, or C-C haloalkyl; a is 2-thiofuryl, R 7 is H, C1-C6 alkyl or C1-C6 haloalkyl; However, R d is C1-C6 alkyl, R 7 is H and R 7 is C1-C6 alkyl, R d is H).

[0050] In one variation, a compound of formula (I), or a salt thereof, is provided, wherein R 1 (i.e., C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 haloalkyl) is in the "S" configuration. In another variation, a compound of formula (I), or a salt thereof, is provided, wherein R 1 (i.e., C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 haloalkyl) is in the "R" configuration. Also included are mixtures of compounds of Formula (I), including racemic or non-racemic mixtures of a given compound, and mixtures of two or more compounds of different chemical formulas.

[0051] In the description herein, it is understood that every description, variation, embodiment, or aspect of a moiety can be combined with every description, variation, embodiment, or aspect of any other moiety as if each and every combination of descriptions were specifically and individually listed. For example, R 1 All descriptions, variations, embodiments, or aspects provided herein with respect to A may be combined with all descriptions, variations, embodiments, or aspects of A in formula (I), as if each and every combination were specifically and individually listed.

[0052] In some embodiments, compounds of Formula (I) are provided, wherein A is [ka] In some embodiments, compounds of Formula (I) are provided, wherein A is [ka] is.

[0053] In some embodiments, compounds of Formula (I) are provided, wherein A is [ka] is.

[0054] In some embodiments of Formula (I), R 1 is C1-C6 alkyl. In other embodiments, R 1 is C-C cycloalkyl. In some embodiments, R 1 is C1-C6 haloalkyl. In certain embodiments, R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 1 is cyclopropyl.

[0055] In some embodiments of Formula (I), R 3 is R 1 and together with the atoms to which they are attached form a 5- or 6-membered carbocyclic ring. 3 is R 1 and together with the atoms to which they are attached form an unsubstituted 5-membered carbocyclic ring. 3 is R 1 and together with the atoms to which they are attached form an unsubstituted 6-membered carbocyclic ring. 3 is R 1 and together with the atoms to which they are attached form a 5-membered carbocyclic ring substituted with 1 to 3 groups selected from the group consisting of halo, CN, —OH, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R 3 is R 1 and together with the atoms to which they are attached form a 6-membered carbocyclic ring substituted with 1 to 3 groups selected from the group consisting of halo, CN, —OH, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, R 3 is R 1and together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring, which is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of halo, CN, —OH, C1-C6 alkyl, and C1-C6 haloalkyl.

[0056] In some embodiments of compounds of Formula (I), L is absent. In other embodiments, L is -CH-. In some embodiments, L is absent and R 1 is C1-C6 alkyl. In other embodiments, L is absent and R 1 is C3-C8 cycloalkyl. In some embodiments, L is absent and R 1 is C1-C6 haloalkyl. In certain embodiments, L is absent and R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, L is absent and R 1 is methyl. In some embodiments, L is absent and R 1 is ethyl. In some embodiments, L is absent and R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, L is absent and R 1 is cyclopropyl.

[0057] In some embodiments of compounds of Formula (I), L is absent and R 3 is R 1 and together with the atom to which they are attached form a 5- or 6-membered carbocyclic ring. In some embodiments, L is absent and R 3 is R 1 and together with the atom to which they are attached form an unsubstituted 5-membered carbocyclic ring. In some embodiments, L is absent and R 3 is R 1and together with the atom to which they are attached form an unsubstituted 6-membered carbocyclic ring. In some embodiments, L is absent and R 3 is R 1 and together with the atoms to which they are attached form a 5-membered carbocyclic ring substituted with 1 to 3 groups selected from the group consisting of halo, CN, —OH, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, L is absent and R 3 is R 1 and together with the atoms to which they are attached form a 6-membered carbocyclic ring substituted with 1 to 3 groups selected from the group consisting of halo, CN, —OH, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, L is absent and R 3 is R 1 and together with the atom to which they are attached form a 5- or 6-membered heterocyclic ring, which is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of halo, CN, —OH, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, L is absent and R 3 is R 1 and together with the atoms to which they are attached form a 5-membered carbocyclic ring, which is unsubstituted or substituted with halo, CN, —OH, C1-C6 alkyl, or C1-C6 haloalkyl; R 2 , R 4 , R 5 , and R 6 In certain embodiments, one or two of R are independently selected from halo, CN, C-C alkyl, and C-C haloalkyl. 3 is R 1 and together with the atoms to which they are attached form an unsubstituted 5-membered carbocyclic ring, R 2 , R 4 , R 5 , and R 6 are each H. In one variation, L is absent and R 3 is R 1 If the carbon having R is in the "S" configuration, 1and together with the atoms to which they are attached form a 5-membered carbocyclic ring. In another variation, L is absent and R 3 is R 1 If the carbon having the 1 and together with the atoms to which they are attached form a five-membered carbocyclic ring.

[0058] In some embodiments, L is -CH- and R 1 is C1-C6 alkyl. In other embodiments, L is -CH2- and R 1 is C3-C8 cycloalkyl. In some embodiments, L is -CH2- and R 1 is C1-C6 haloalkyl. In certain embodiments, L is -CH2- and R 1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, L is -CH- and R 1 In some embodiments, L is -CH- and R 1 In some embodiments, L is -CH- and R 1 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, L is —CH— and R 1 In some embodiments of the compound of Formula (I), L is -CH- and R 3 is R 1 and together with the atom to which they are attached form a 5- or 6-membered carbocyclic ring. In some embodiments, L is -CH- and R 3 is R 1 and together with the atom to which they are attached form an unsubstituted 5-membered carbocyclic ring. In some embodiments, L is -CH- and R 3 is R 1 and together with the atom to which they are attached form an unsubstituted 6-membered carbocyclic ring. In some embodiments, L is -CH- and R 3is R 1 and together with the atoms to which they are attached form a 5-membered carbocyclic ring substituted with 1 to 3 groups selected from the group consisting of halo, CN, —OH, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, L is —CH2— and R 3 is R 1 and together with the atoms to which they are attached form a 6-membered carbocyclic ring substituted with 1 to 3 groups selected from the group consisting of halo, CN, —OH, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, L is —CH2— and R 3 is R 1 and together with the atom to which they are attached form a 5- or 6-membered heterocyclic ring, which is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of halo, CN, —OH, C1-C6 alkyl, and C1-C6 haloalkyl. In some embodiments, L is —CH2— and R 3 is R 1 and together with the atoms to which they are attached form a 5-membered carbocyclic ring, which is unsubstituted or substituted with halo, CN, —OH, C1-C6 alkyl, or C1-C6 haloalkyl; R 2 , R 4 , R 5 , and R 6 In certain embodiments, one or two of L is -CH- and R 3 is R 1 and together with the atoms to which they are attached form an unsubstituted 6-membered carbocyclic ring, R 2 , R 4 , R 5 , and R 6 are each H. In one variation, L is -CH- and R 3 is R 1 If the carbon having R is in the "S" configuration, 1 and together with the atom to which they are attached form a 5- or 6-membered carbocyclic ring. In another variation, L is -CH- and R3 is R 1 If the carbon having the 1 and together with the atoms to which they are attached form a 5- or 6-membered carbocyclic ring.

[0059] In some embodiments of Formula (I), A is [ka] and R a In another embodiment of formula (I), A is 2-furyl. [ka] and R a In some embodiments of Formula (I), A is 2-pyridinyl. [ka] and R a In another embodiment of formula (I), A is 2-pyrimidinyl. [ka] and R a In yet another embodiment of Formula (I), A is 4-pyrimidinyl. [ka] and R a is 2-pyrazinyl.

[0060] In some embodiments of Formula (I), A is [ka] and R a In another embodiment of formula (I), A is 2-furyl. [ka] and R aIn some embodiments of Formula (I), A is 2-pyridinyl. [ka] and R a In another embodiment of formula (I), A is 2-pyrimidinyl. [ka] and R a In yet another embodiment of Formula (I), A is 4-pyrimidinyl. [ka] and R a is 2-pyrazinyl.

[0061] In another embodiment of Formula (I), A is [ka] and R a In another embodiment of formula (I), A is 2-furyl. [ka] and R a In some embodiments of Formula (I), A is 2-pyridinyl. [ka] and R a In another embodiment of formula (I), A is 2-pyrimidinyl. [ka] and R a In yet another embodiment of Formula (I), A is 4-pyrimidinyl. [ka] and R a is 2-pyrazinyl.

[0062] In certain embodiments of Formula (I), -- is a bond, whereby R 3 is R 1 and together with the atom to which they are attached form a 6-membered carbocyclic ring. In some variations, the 6-membered carbocyclic ring is unsubstituted. In other variations, the 6-membered carbocyclic ring is substituted. In still other variations, the 6-membered carbocyclic ring is substituted with 1 to 3 groups selected from the group consisting of halo, -CN, -OH, C1-C6 alkyl, and C1-C6 haloalkyl.

[0063] In some embodiments of Formula (I), -- is a bond, whereby R 3 is R 1 and together with the atom to which they are attached form a 5-membered carbocyclic ring. In some variations, the 5-membered carbocyclic ring is unsubstituted. In other variations, the 5-membered carbocyclic ring is substituted. In still other variations, the 5-membered carbocyclic ring is substituted with 1 to 3 groups selected from the group consisting of halo, —CN, —OH, C1-C6 alkyl, and C1-C6 haloalkyl, and R 2 , R 4 , R 5 , and R 6 At least one of is halo, CN, or C1-C6 alkyl.

[0064] In some embodiments of Formula (I), A is

[0065] [ka] and R a is 2-furyl, L is absent, and R 1 is C1-C6 alkyl or a bond, whereby R 3 is R 1 and together with the atoms to which they are attached form a 5- or 6-membered carbocyclic ring, provided that when a 5-membered carbocyclic ring is formed, R 2 , R 4 , R 5 , and R 6At least one of is halo, CN, C1-C6 alkyl, or C1-C6 haloalkyl.

[0066] In certain embodiments of Formula (I), R d is C1-C6 alkyl, R 7 is H. In another embodiment of formula (I), R 7 is C1-C6 alkyl, R d is H.

[0067] In some embodiments of the compounds of Formula (I), R 2 , R 3 , R 4 , R 5 , and R 6 are each independently H, halo, CN, C-C alkyl, or C-C haloalkyl. 2 , R 3 , R 4 , R 5 , and R 6 are each independently H, Cl, CN, or CF. In some embodiments, R 4 and R 5 are each independently Cl, Br, I, CN, C-C alkyl, or C-C haloalkyl. 2 , R 3 , R 4 , R 5 , and R 6 is other than H. In some embodiments, one of R 2 , R 3 , R 4 , R 5 , and R 6 Two of R are other than H. In some embodiments, R 2 , R 3 , R 4 , R 5 , and R 6 At least two of R 2 , R 3 , R 4 , R5 , and R 6 In some embodiments, one of R 6 is CN. In some embodiments, R 2 , R 3 , R 4 , R 5 , and R 6 In some embodiments, one of R 2 , R 3 , R 4 , R 5 , and R 6 In some embodiments, two of R 2 and R 6 are each CF3 or R 4 and R 5 are each CF3 or R 3 and R 6 are each CF. In some embodiments, R 2 , R 3 , R 4 , R 5 , and R 6 In some embodiments, one or two of R 4 and R 5 are each Cl. In other embodiments, R 2 and R 3 are each Cl. In still other embodiments, R 2 and R 3 are each F. In some embodiments, R 2 and R 3 One of them is F and the other is R 2 and R 3 In some embodiments, one of R 2 and R 6 are each F. In other embodiments, R 2 and R 6 are each Cl. In some embodiments, R 2 and R 6 One of them is F and the other is R 2 and R6 In some embodiments, one of R 2 , R 4 , R 5 , and R 6 are each H. In some embodiments, R 2 , R 3 , R 4 , R 5 , and R 6 are other than H. In certain embodiments, R 2 , R 3 , and R 6 is other than H. In some embodiments, R 2 , R 3 , and R 6 and each is halo. In certain embodiments, R 2 , R 3 , and R 6 are F respectively.

[0068] In some embodiments of Formula (I), [ka] teeth, [ka] where R 2 and R 6 are each C1-C6 haloalkyl. In some embodiments, [ka] teeth, [ka] where R 2 and R 6 are each independently selected from the group consisting of halo, C-C alkyl, and C-C haloalkyl. [ka] teeth, [ka] where R 2 and R 6 are each independently selected from the group consisting of Cl, C-C alkyl, and C-C haloalkyl. [ka] teeth, [ka] where R 2 and R 6 are each independently Cl or F. In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] where R 2 and R 6 are each independently F. In some embodiments, [ka] teeth, [ka] where R 2 and R 6 One of them is F and the other is R 2 and R 6 In some embodiments, one of [ka] teeth, [ka] where R 2 and R 3 and each is halo. [ka] teeth, [ka] where R 5 and R 6 are each independently selected from the group consisting of Cl, Br, I, CN, C-C alkyl, and C-C haloalkyl. [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In another embodiment, [ka] teeth, [ka] In yet another embodiment, [ka] teeth, [ka] is.

[0069] In some embodiments of the compounds of Formula (I), R a is a 5- or 6-membered heteroaryl, which is unsubstituted or substituted with 1 to 4 groups selected from OH, halo, and C1-C6 alkyl. a is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, isoxazolyl, oxazolyl, oxadiazolyl, thiophenyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl, each of which is unsubstituted or substituted with 1 to 4 groups selected from the group consisting of OH, halo, C1-C6 alkyl, and C1-C6 alkoxy. a is selected from the group consisting of 2-furyl, 2-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, and 2-pyrazinyl, each of which is unsubstituted or substituted with 1 to 4 groups selected from the group consisting of OH, halo, C1-C6 alkyl, and C1-C6 alkoxy.

[0070] In some embodiments, R a is a 5- or 6-membered heteroaryl containing 1 heteroatom. In some embodiments, R 2 , R 3 , R 4 , R 5 , and R 6 When at least two of R are C1-C6 haloalkyl, a is a 6-membered heteroaryl containing at least two heteroatoms. In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt thereof, R d is H or C1-C6 alkyl, R 1is C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 haloalkyl; L is -CH2- or absent; -- is a bond or is absent, R 2 , R 3 , R 4 , R 5 , and R 6 are each independently H, halo, CN, C-C alkyl, or C-C haloalkyl; R 2 , R 3 , R 4 , R 5 , and R 6 at least two of are halo, CN, C1-C6 alkyl, or C1-C6 haloalkyl; and / or R 2 , R 3 , R 4 , R 5 , and R 6 One of the is CN or Or R 2 , R 4 , R 5 , and R 6 are each independently H, halo, CN, C-C alkyl, or C-C haloalkyl; -- is a bond, so R 3 But R 1 and together with the atoms to which they are attached form a 5- or 6-membered carbocyclic ring, which 5- or 6-membered carbocyclic ring is unsubstituted or substituted with 1 to 3 groups selected from the group consisting of halo, CN, —OH, C1-C6 alkyl, and C1-C6 haloalkyl; A is,

[0071] [ka] and R ais a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is unsubstituted or substituted with 1 to 4 groups selected from the group consisting of OH, halo, C1-C6 alkyl, and C1-C6 alkoxy; However, R 2 , R 3 , R 4 , R 5 , and R 6 When at least two of R are C1-C6 haloalkyl, a is a 6-membered heteroaryl containing at least two heteroatoms, provided that A is

[0072] [ka] and R a is 2-furyl or 2-thiofuryl, at least one of (i.) to (vi.) applies; (i.) L is absent, R 1 is C1-C6 alkyl, (ii.) -- is a bond, whereby R 3 But R 1 and together with the atoms to which they are attached form a 5- or 6-membered carbocyclic ring, provided that when a 5-membered carbocyclic ring is formed, R 2 , R 4 , R 5 , and R 6 at least one of is halo, CN, C1-C6 alkyl, or C1-C6 haloalkyl; (iii.)R 2 , R 3 , R 4 , R 5 , and R 6 One of them is CN, (iv.)R 4 and R 5 are each independently Cl, Br, I, CN, C1-C6 alkyl, or C1-C6 haloalkyl; (v.) R 2 and R 3 are each Cl, (vi.)R2 , R 3 , R 4 , R 5 , and R 6 at least one of R is F, Br, I, CN, or C-C haloalkyl; a is 2-thiofuryl, R 7 is H, C1-C6 alkyl or C1-C6 haloalkyl; However, R d is C1-C6 alkyl, R 7 is H and R 7 is C1-C6 alkyl, R d is H.

[0073] In some embodiments, A is

[0074] [ka] and R a is a 5- or 6-membered heteroaryl that is unsubstituted or substituted with 1 to 4 groups selected from the group consisting of OH, halo, C1-C6 alkyl, and C1-C6 alkoxy. In some embodiments, A is

[0075] [ka] and R a is 2-furyl, 2-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, and 2-pyrazinyl, each of which is unsubstituted or substituted with 1 to 4 groups selected from the group consisting of OH, halo, and C1-C6 alkyl. In some embodiments, A is

[0076] [ka] and R a is a 2-frill.

[0077] In some embodiments of the compounds of Formula (I), A is

[0078] [ka] and R a is a 5- or 6-membered heteroaryl, and R a In some embodiments, A is a 5- or 6-membered heteroaryl, unsubstituted or substituted with 1 to 4 groups selected from the group consisting of OH, halo, and C1-C6 alkyl.

[0079] [ka] and R a is 2-furyl, 2-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, and 2-pyrazinyl, each of which is unsubstituted or substituted with 1 to 4 groups selected from the group consisting of OH, halo, and C1-C6 alkyl. In some embodiments, A is

[0080] [ka] and R a is 2-pyrazinyl.

[0081] In some embodiments of the compounds of Formula (I), A is

[0082] [ka] and R a is a 5- or 6-membered heteroaryl, and R a In some embodiments, A is a 5- or 6-membered heteroaryl, unsubstituted or substituted with 1 to 4 groups selected from the group consisting of OH, halo, and C1-C6 alkyl.

[0083] [ka] and R ais 2-furyl, 2-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, and 2-pyrazinyl, each of which is unsubstituted or substituted with 1 to 4 groups selected from the group consisting of OH, halo, and C1-C6 alkyl. In some embodiments, A is

[0084] [ka] and R a is a 2-frill.

[0085] In some embodiments of any of the formulas provided herein, R d and R 7 is H and A is

[0086] [ka] and R a is 2-frill and R 1 is methyl and L is absent. In some embodiments of any of the formulas provided herein, R d is methyl and R 7 is H and A is

[0087] [ka] and R a is 2-frill and R 1 is methyl and L is absent. In some embodiments of any of the formulas provided herein, R d is H and R 7 is methyl and A is

[0088] [ka] and R a is 2-frill and R 1 is methyl and L is absent. In some embodiments of any of the formulas provided herein, R dand R 7 is H and A is

[0089] [ka] and R a is 2-furyl and -- is a bond, so that R 3 But R 1 and together with the atoms to which they are attached form an unsubstituted 6-membered carbocyclic ring. In some embodiments of any of the formulas provided herein, R d and R 7 is H and A is

[0090] [ka] and R a is 2-furyl and -- is a bond, so that R 3 But R 1 and together with the atoms to which they are attached form an unsubstituted 5-membered carbocyclic ring.

[0091] In some embodiments of any of the formulas provided herein, R d and R 7 is H and A is

[0092] [ka] and R a is 2-frill and R 1 is methyl and L is absent. In some embodiments of any of the formulas provided herein, R d is methyl and R 7 is H and A is

[0093] [ka] and R a is 2-frill and R 1is methyl and L is absent. In some embodiments of any of the formulas provided herein, R d is H and R 7 is methyl and A is

[0094] [ka] and R a is 2-frill and R 1 is methyl and L is absent. In some embodiments of any of the formulas provided herein, R d and R 7 is H and A is

[0095] [ka] and R a is 2-furyl and -- is a bond, so that R 3 But R 1 and together with the atoms to which they are attached form an unsubstituted 6-membered carbocyclic ring. In some embodiments of any of the formulas provided herein, R d and R 7 is H and A is

[0096] [ka] and R a is 2-furyl and -- is a bond, so that R 3 But R 1 and together with the atoms to which they are attached form an unsubstituted 5-membered carbocyclic ring. In some embodiments of any of the formulas provided herein, R d and R 7 is H and A is

[0097] [ka] and R a is 2-pyrazinyl and R 1is methyl and L is absent.

[0098] In some embodiments of any of the formulas provided herein, R d and R 7 is H and A is

[0099] [ka] and R a is 2-frill and R 1 is methyl and L is absent. In some embodiments of any of the formulas provided herein, R d is methyl and R 7 is H and A is

[0100] [ka] and R a is 2-frill and R 1 is methyl and L is absent. In some embodiments of any of the formulas provided herein, R d is H and R 7 is methyl and A is

[0101] [ka] and R a is 2-frill and R 1 is methyl and L is absent. In some embodiments of any of the formulas provided herein, R d and R 7 is H and A is

[0102] [ka] and R a is 2-furyl and -- is a bond, so that R 3 But R 1and together with the atoms to which they are attached form an unsubstituted 6-membered carbocyclic ring. In some embodiments of any of the formulas provided herein, R d and R 7 is H and A is

[0103] [ka] and R a is 2-furyl and -- is a bond, so that R 3 But R 1 and together with the atoms to which they are attached form an unsubstituted 5-membered carbocyclic ring.

[0104] In some variations of the embodiments described herein, the compound of formula (I) is not any of the following compounds:

[0105] N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)propyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide, 5-Acetyl-N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-3-(3-fluorophenyl)-1,2,4-oxadiazole-5-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(pyridin-4-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-{1-[2,4-bis(trifluoromethyl)phenyl]ethyl}-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-{1-[2,4-bis(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}-5-tert-butyl-1,2-oxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-[3,3'-bipyridine]-5-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(2,4-difluorophenyl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-imidazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(2,3-dihydro-1H-inden-2-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(4fluorophenyl)nicotinamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-phenylnicotinamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(5-methylfuran-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide, N-(1-(2,6-dichlorobenzyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(4-cyanobenzyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(4-cyano-3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(3,5-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-3-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(3-chloropyridin-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(3-chloropyridin-2-yl)isoxazole-3-carboxamide, N-(1-((2,4-bis(trifluoromethyl)phenyl)(cyclopropyl)methyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(3-chloropyridin-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyridin-3-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)nicotinamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-5-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-3-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide N-(1-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-5-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5'-carboxamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5'-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5'-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5'-carboxamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-5-methyl-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5'-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-3-methyl-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5'-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5'-carboxamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-[2,3'-bipyridine]-5'-carboxamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(pyridin-2-yl)isoxazole-5-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-5-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-4-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-2-(furan-2-yl)thiazole-5-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-[2,4'-bipyridine]-2'-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-[2,3'-bipyridine]-6'-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(pyridin-2-yl)acrylamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(2-methoxyphenyl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(2-methoxyphenyl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)phenyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-5-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-3-methyl-1H-pyrazol-4-yl)-3-(furan-2-yl)acrylamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyrimidin-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-N-methyl-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-5-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-4-methyl-2-(pyridin-2-yl)thiazole-5-carboxamide, N-(1-(1-(2-fluoro-4-(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-1-methyl-3-(pyridin-2-yl)-1H-pyrazole-5-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-1-methyl-5-(pyridin-2-yl)-1H-pyrazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(pyrazin-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(6-methylpyridin-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(6-methylpyridin-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-5-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)-1H-pyrazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-1-(pyridin-2-yl)-1H-1,2,3-triazole-4-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yl)oxazole-4-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yl)oxazole-5-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(pyrimidin-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-2-(pyridin-2-ylamino)thiazole-5-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyrazin-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)-1,3,4-oxadiazole-2-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-4-methyl-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyrazin-2-yl)-1,3,4-thiadiazole-2-carboxamide, N-(1-(1-(4-fluoro-2-(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)picolinamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)pyrazine-2-carboxamide, N-(1-(2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)-1,3,4-thiadiazole-2-carboxamide, N-(1-(2,6-dichlorobenzyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide, N-(1-(2,6-dichlorobenzyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(2,6-dichlorobenzyl)-1H-pyrazol-4-yl)-2-(furan-2-yl)thiazole-5-carboxamide, N-(1-(2,6-dichlorobenzyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)-1,3,4-thiadiazole-2-carboxamide, N-(1-(2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, N-(1-(2,4-bis(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-5-(pyridin-2-yl)-1,3,4-oxadiazole-2-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyrazin-2-yl)-1,3,4-thiadiazole-2-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-4-methyl-5-(pyridin-2-yl)isoxazole-3-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(pyrimidin-4-yl)-1,3,4-thiadiazole-2-carboxamide, N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(pyridin-2-yl)-1,3,4-thiadiazole-2-carboxamide, and N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)-1,3,4-thiadiazole-2-carboxamide, or a pharmaceutically acceptable salt thereof.

[0106] Representative compounds are listed in Table 1.

[0107] [Table 1] TIFF2026041801000078.tif243164TIFF2026041801000079.tif230164TIFF2026041801000080.tif192164

[0108] In some embodiments, provided herein are compounds set forth in Table 1, or pharmaceutically acceptable salts thereof, and uses thereof.

[0109] The embodiments and variations described herein, where applicable, are suitable for compounds of any formula detailed herein.

[0110] N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; 5-(furan-2-yl)-N-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide; N-(1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; 5-(furan-2-yl)-N-(1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide; N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)-1,3,4-thiadiazole-2-carboxamide; N-(1-(1-(2,6-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(pyrazin-2-yl)isoxazole-5-carboxamide; 5-(pyrazin-2-yl)-N-(1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide; N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide; N-(1-(1-(2,6-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide; and N-(1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide, a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof. Also provided herein are any and all stereoisomers of the compounds presented herein, including, where applicable, geometric isomers (e.g., cis / trans or E / Z isomers), enantiomers, diastereomers, or mixtures thereof in any ratio, including racemic mixtures.

[0111] The embodiments and variations described herein, where applicable, are suitable for compounds of any formula detailed herein.

[0112] All representative examples of compounds detailed herein, including intermediate and final compounds according to the present disclosure, are presented herein. In one aspect, it is understood that any of the compounds, including intermediate compounds that may be isolated and administered to an individual, if applicable, may be used in the methods detailed herein.

[0113] The compounds provided herein may exist as salts even if no salts are provided, and it should be understood that the present disclosure encompasses all salts and solvates of the compounds provided herein, as well as non-salt and non-solvate forms of the compounds, as will be fully understood by those skilled in the art.In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.When one or more tertiary amine moieties are present in the compound, N-oxides are also provided and described.

[0114] Where tautomeric forms may exist for any of the compounds described herein, only one or some of the tautomeric forms may be explicitly shown, but each and every tautomeric form is intended. The specifically shown tautomeric form may or may not be the predominant form in solution or when used in accordance with the methods described herein.

[0115] The present disclosure also encompasses any or all stereochemical forms, including any enantiomeric or diastereomeric forms, of the compounds described. Compounds of any formula provided herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of compounds of the general formula, and mixtures thereof in any ratio, are contemplated within the scope of the formula. Thus, any formula provided herein is intended to represent the racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio, unless a specific stereochemistry is otherwise indicated. When a compound in Table 1 is shown in a specific stereochemical configuration, any alternative stereochemical configuration of the compound and mixtures of the compound's stereoisomers in any ratio are also provided herein. For example, if a compound in Table 1 has a stereocenter in the "S" stereochemical configuration, enantiomers of the compound in which the stereocenter is in the "R" stereochemical configuration are also provided herein. Similarly, if a compound in Table 1 has a stereocenter in the "R" configuration, then enantiomers of the compound in the "S" stereochemical configuration are also provided herein. Mixtures of compounds having both the "S" and "R" stereochemical configurations are also provided. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. For example, compounds of any formula given herein may contain bonds with restricted rotation and therefore exist in different geometric configurations. When a compound in Table 1 is designated as a particular geometric isomer (e.g., E or Z isomer, or cis or trans isomer), then any alternate geometric configuration of the compound, and mixtures of geometric isomers of the compound in any ratio, are also provided herein. For example, when a compound in Table 1 is designated as a "Z" isomer, then the "E" isomer of the compound is also provided herein. Similarly, when a compound in Table 1 is designated as an "E" isomer, then the "Z" isomer of the compound is also provided herein. Mixtures of compounds having both "E" and "Z" stereochemical configurations are also provided, and the mixtures are in any ratio.Similarly, when a compound in Table 1 is designated as a "cis" isomer, the "trans" isomer of the compound is also provided herein, and when a compound is designated as a "trans" isomer, the "cis" isomer of the compound is also provided herein. Mixtures of compounds having both "cis" and "trans" stereochemical configurations are also provided, and the mixtures are in any ratio. All forms of the compounds, e.g., crystalline or amorphous forms of the compounds, are also encompassed by the present invention. Compositions comprising the compounds of the present invention also contemplate, for example, compositions of substantially pure compounds containing a particular stereochemical form thereof, or compositions comprising mixtures of the compounds of the present invention in any ratio containing two or more stereochemical forms, such as racemic or non-racemic mixtures.

[0116] The present invention also contemplates the isotopically labeled and / or isotopically enriched form of the compounds described herein.The compounds herein may contain unnatural proportions of atomic isotopes in one or more of the atoms that constitute such compounds.In some embodiments, the compounds are isotopically labeled, for example, isotopically labeled compounds of formula (I) described herein or variants thereof, in which a fraction of one or more atoms is replaced by an isotope of the same element.Exemplary isotopes that can be incorporated into the compounds of the present invention include: 2 H, 3 H, 11 C. 13 C. 14 C 13 N, 15 O. 17 O. 32 P, 35 S, 18 F, 36 These include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, and chlorine, such as Cl. Certain isotopically labeled compounds, e.g. 3 H and 14 C) is useful in compound or substrate tissue distribution studies. 2Incorporation of heavier isotopes, such as H), can offer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements, and therefore may be preferred in some cases.

[0117] Isotopically labeled compounds of the present invention can generally be prepared by standard methods and techniques known to those skilled in the art, or by procedures similar to those described in the accompanying examples substituting the appropriate isotopically labeled reagent for the corresponding unlabeled reagent.

[0118] The present invention also includes metabolites of any or all of the described compounds. Metabolites can include any chemical species produced by biotransformation of any of the described compounds, for example, intermediates and products of metabolism of a compound as produced in vivo after administration to humans.

[0119] An article of manufacture is provided that includes a compound described herein, or a salt or solvate thereof, in a suitable container, which may be a vial, jar, ampoule, preloaded syringe, IV bag, and the like.

[0120] Preferably, the compounds detailed herein are orally bioavailable, however, the compounds may also be formulated for parenteral (e.g., intravenous) administration.

[0121] One or several compounds described herein can be used to prepare medicaments by combining the compound(s) as active ingredient with pharmacologically acceptable carrier known in the art.Depending on the therapeutic form of the medicament, carrier can be in various forms.In one variation, the preparation of the medicament is for use in any of the methods disclosed herein, for example, for the treatment of cancer.

[0122] General synthesis method The compounds of the present invention can be prepared by several processes as generally described below. In the process descriptions below, the symbols when used in the formulae shown should be understood to represent those groups as described above with respect to the formulae herein.

[0123] If it is desired to obtain a specific enantiomer of a compound, this can be achieved from the corresponding mixture of enantiomers by using any suitable conventional procedure for separating or resolving enantiomers.Thus, for example, diastereomeric derivatives can be produced by reacting a mixture of enantiomers, such as a racemate, with an appropriate chiral compound.The diastereomers can then be separated by any convenient means, for example, by crystallization, and the desired enantiomer is recovered.In another resolution process, a racemate can be separated using chiral high-performance liquid chromatography.Alternatively, if desired, a specific enantiomer can be obtained by using an appropriate chiral intermediate in one of the processes described.

[0124] Chromatography, recrystallization, and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular isomer of a compound or to otherwise purify the product of a reaction.

[0125] Solvates and / or polymorphs of the compounds provided herein or their pharmaceutically acceptable salts are also contemplated. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and are often formed during the crystallization process. Hydrates form when the solvent is water, or alcoholates form when the solvent is alcohol. Polymorphs include different crystal packing arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stability, and / or solubility. Various factors, such as the recrystallization solvent, crystallization rate, and storage temperature, may govern a single crystalline form.

[0126] In some embodiments, compounds of Formula (I) can be synthesized according to Scheme 1. Scheme 1 [ka] where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R d and A is as defined for formula (I), or any variation thereof detailed herein.

[0127] An exemplary embodiment of the preparation method in Scheme 1 is shown in Scheme 1a. Scheme 1a [ka] where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R d , and R a is as defined for formula (I) or any variation thereof detailed herein.

[0128] In some embodiments, compounds of Formula (I) can be synthesized according to Scheme 2. Scheme 2 [ka] where A, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R d and n is as defined for formula (I) or any variation thereof detailed herein, and X is a halogen.

[0129] An exemplary embodiment of the preparation method in Scheme 2 is shown in Scheme 2a. Scheme 2a [ka] where A, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R d and n is as defined for formula (I) or any variation thereof detailed herein, and X is a halogen.

[0130] In some embodiments, compounds of Formula (I) can be synthesized according to Scheme 3. Scheme 3 [ka] where A, R 2 , R 4 , R 5 , R 6 , R 7 , and R d is as defined for formula (I) or any variation thereof detailed herein.

[0131] An exemplary embodiment of the preparation method in Scheme 3 is shown in Scheme 3a. Scheme 3a [ka] where A, R 2 , R 4 , R 5 , R 6 , R 7 , and R d is as defined for formula (I) or any variation thereof detailed herein.

[0132] In some embodiments, compounds of Formula (I) can be synthesized according to Scheme 4. Scheme 4 [ka] where A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R d is as defined for formula (I) or any variation thereof detailed herein, and X is a halogen.

[0133] Specific examples are provided in the Examples section below. It should be understood that the above schemes can be modified to arrive at various compounds of the invention by the selection of appropriate reagents and starting materials. For a general discussion of protecting groups and their use, see P.G.M.Wuts and T.W.Greene, "Greene's Protective Groups in Organic Synthesis 4." th See, e.g., Wiley-Interscience, New York, 2006.

[0134] Pharmaceutical Compositions and Formulations Pharmaceutical compositions of any of the compounds described herein are encompassed by the present disclosure.Accordingly, the present disclosure includes pharmaceutical compositions comprising the compounds detailed herein or their pharmaceutically acceptable salts and pharmaceutically acceptable carriers or excipients.In one aspect, the pharmaceutically acceptable salt is an acid addition salt, such as a salt formed with an inorganic or organic acid.The pharmaceutical composition can be in a form suitable for oral, buccal, parenteral, nasal, topical, or rectal administration, or in a form suitable for inhalation administration.

[0135] The compounds detailed herein may be in one aspect in purified form, and compositions comprising the compounds in purified form are described herein. Compositions comprising the compounds detailed herein or salts thereof are provided, such as compositions of substantially pure compounds. In some embodiments, the compositions comprising the compounds detailed herein or salts thereof are in substantially pure form.

[0136] In one variation, the compounds herein are synthetic compounds prepared for administration to an individual. In another variation, compositions containing the compounds in substantially pure form are provided. In another variation, the present disclosure encompasses pharmaceutical compositions containing the compounds detailed herein and a pharmaceutically acceptable carrier. In another variation, methods of administering the compounds are provided. Purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for any of the compounds or forms thereof detailed herein.

[0137] The compounds or salts thereof detailed herein can be formulated for any available delivery route, including oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g., intramuscular, subcutaneous, or intravenous), topical, or transdermal delivery forms. The compounds or salts thereof can be formulated with a suitable carrier to provide delivery forms including, but not limited to, tablets, caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, poultices (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal sprays or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs.

[0138] One or several compounds or salts thereof described herein can be used to prepare formulations such as pharmaceutical preparations by combining the compound(s) or their salts as the active ingredient with a pharmaceutically acceptable carrier such as those described above. Depending on the treatment form of the system (e.g., transdermal patch vs. oral tablet), the carrier can be in various forms. In addition, pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, adjusters, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants. Preparations containing compounds can also contain other substances with valuable therapeutic properties. Pharmaceutical preparations can be prepared by known pharmaceutical methods. Suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 2014, incorporated herein by reference. th ed. (2000).

[0139] The compounds described herein can be administered to individuals in the form of commonly accepted oral compositions, such as hard or soft shell gel capsules, tablets, and coated tablets, emulsions, or suspensions. Examples of carriers that can be used to prepare such compositions include lactose (milk sugar), corn starch or its derivatives, talc, stearates or their salts, etc. Acceptable carriers for soft shell gel capsules include vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. In addition, pharmaceutical preparations can include preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, adjusters, and salts for adjusting osmotic pressure, buffers, coating agents, or antioxidants.

[0140] Any of the compounds described herein can be formulated in a tablet in any dosage form described, for example, a compound as described herein or a pharmaceutically acceptable salt thereof can be formulated as a 10 mg tablet.

[0141] Also described herein are compositions comprising the compounds provided herein. In one variation, the composition comprises the compound or a salt thereof and a pharmaceutically acceptable carrier or excipient. In another variation, a composition of substantially pure compound is provided.

[0142] Instructions and Use The compounds and compositions detailed herein, for example, pharmaceutical compositions comprising a compound of any formula provided herein or a salt thereof and a pharmaceutically acceptable carrier or excipient, can be used in the methods of administration and treatment as provided herein. The compounds and compositions can also be used in in vitro methods, such as in vitro methods in which the compound or composition is administered to cells for screening purposes and / or to perform quality control assays.

[0143] In some embodiments, provided herein are methods for modulating the ATF6 pathway. In some embodiments, provided herein are methods for modulating ATF6. In some embodiments, provided herein are methods for activating the ATF6 pathway. In some embodiments, provided herein are methods for activating ATF6. In some embodiments, provided herein are methods for inhibiting the ATF6 pathway. In some embodiments, provided herein are methods for inhibiting ATF6. In some embodiments, ATF6 is ATF6α. The compounds or salts thereof described herein and the compositions described herein are believed to be effective in inhibiting the ATF6 pathway, ATF6, and / or ATF6α.

[0144] In some embodiments, methods for modulating the ATF6 pathway, ATF6, or ATF6α include administering or delivering a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, to a cell comprising ATF6 or ATF6α. In some embodiments, methods for activating the ATF6 pathway, ATF6, or ATF6α include administering or delivering a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, to a cell comprising ATF6 or ATF6α. In some embodiments, methods for inhibiting the ATF6 pathway, ATF6, or ATF6α include administering or delivering a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, to a cell comprising ATF6 or ATF6α. In some embodiments, the cell is an abnormal cell, such as a cancer cell. In some embodiments, the cell has an activated ATF6 pathway. In some embodiments, the cell is exposed to an ER stress-inducing condition. Some ER stress-inducing conditions include glucose deprivation, abnormal Ca 2+ Regulation, viral infection, hypoxia, and exposure to ER stress-inducing molecules, such as thapsigargin, ionomycin, or tunicamycin, are known in the art.

[0145] In some embodiments, the method for modulating the ATF6 pathway, ATF6, or ATF6α comprises administering or delivering to a tumor a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the method for activating the ATF6 pathway, ATF6, or ATF6α comprises administering or delivering to a tumor a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In some embodiments, the method for inhibiting the ATF6 pathway, ATF6, or ATF6α comprises administering or delivering to a tumor a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0146] In some embodiments, regulating the ATF6 pathway, ATF6, or ATF6α comprises regulating the expression of target genes of ATF6 and / or ATF6α. In some embodiments, regulating the ATF6 pathway, ATF6, or ATF6α comprises regulating the expression of ATF6α target genes. In some embodiments, the expression of target genes of ATF6 and / or ATF6α is regulated by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 98%. In some embodiments, activating the ATF6 pathway, ATF6, or ATF6α comprises activating the expression of target genes of ATF6 and / or ATF6α. In some embodiments, activating the ATF6 pathway, ATF6, or ATF6α comprises activating the expression of target genes of ATF6 and / or ATF6α. In some embodiments, expression of target genes of ATF6 and / or ATF6α is activated by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 98%. In some embodiments, inhibiting the ATF6 pathway, ATF6, or ATF6α comprises inhibiting expression of target genes of ATF6 and / or ATF6α. In some embodiments, inhibiting the ATF6 pathway, ATF6, or ATF6α comprises inhibiting expression of ATF6α target genes. In some embodiments, expression of target genes of ATF6 and / or ATF6α is inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 98%.

[0147] In some embodiments, a target gene of ATF6 and / or ATF6α comprises a promoter containing an ER stress response element (ERSE). In some embodiments, the promoter comprises a sequence sharing at least about 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with CCAATCGGCGGCGGCCACG (SEQ ID NO: 1). In some embodiments, the promoter comprises SEQ ID NO: 1. In some embodiments, a target gene of ATF6 and / or ATF6α is GRP78, HERPUD1, or ERO1B. In some embodiments, an ATF6α target gene is GRP78. Modulation, activation, or inhibition of expression of a target gene of ATF6 and / or ATF6α can be determined by methods known in the art, for example, by detecting mRNA of the target gene using techniques such as PCR, qPCR, or Northern blotting, or by detecting a polypeptide gene product, such as by Western blotting or mass spectrometry.

[0148] In some embodiments, the compound, salt thereof, or composition inhibits the ATF6 pathway, ATF6, or ATF6α with an IC of less than about 10 μM, e.g., less than about 5 μM, 2 μM, 1 μM, 900 nM, 800 nM, 700 nM, or 600 nM. 50 In some embodiments, the compound, salt thereof, or composition modulates, activates, or inhibits the ATF6 pathway, ATF6, or ATF6α with an IC50 of about 10 nM to 5 μM, e.g., about 50 nM to 2 μM, 100 nM to 1 μM, or 20 nM to 1 μM. 50 The half-maximal inhibitory concentration (IC 50 ) is a measure of the effectiveness of a substance in inhibiting a specific biological or biochemical function. 50 IC is a quantitative measure of how much inhibitor is required to half-inhibit a given biological process or component of a process, e.g., an enzyme, cell, cell receptor, or microorganism. 50 Methods for determining in vitro and in vivo are known in the art.

[0149] In some embodiments, the compounds or salts thereof described herein and compositions described herein are administered in an amount such that ATF6β activity is not modulated (activated or inhibited) or is modulated (activated or inhibited) to a lesser extent. In some embodiments, the modulation (activation or inhibition) of ATF6α is at least or at least about 2-fold greater than the inhibition of ATF6β activity, for example, at least or at least about 3-fold, 4-fold, 5-fold, 8-fold, 10-fold, 15-fold, 30-fold, 50-fold, 60-fold, 75-fold, or 100-fold greater.

[0150] Provided herein are methods of treating a disease in an individual, the method comprising administering to the individual an effective amount of a compound of formula (I), or any embodiment or variation or aspect thereof (collectively, a compound of formula (I) or the present compound or compounds detailed or described herein), or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, provided herein are methods for treating a disease mediated by the ATF6 pathway in an individual, comprising administering to the individual an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods for treating a disease mediated by activation of the ATF6 pathway in an individual, comprising administering to the individual an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods for treating a disease mediated by activation of ATF6 in an individual, comprising administering to the individual an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods for treating a disease mediated by activation of ATF6α in an individual, comprising administering to the individual an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0152] In some embodiments, provided herein are methods for treating a disease in an individual characterized by activation of the ATF6 pathway, comprising administering to the individual an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods for treating a disease in an individual characterized by activation of ATF6, comprising administering to the individual an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods for treating a disease in an individual characterized by activation of ATF6α, comprising administering to the individual an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein are methods for treating a disease in an individual characterized by increased expression of an ATF6 target gene, comprising administering to the individual an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, provided herein is a method for treating a disease characterized by increased expression of an ATF6α target gene in an individual, comprising administering to the individual an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the increased expression is compared to non-diseased tissues or cells.

[0153] The compound or its salt is believed to be effective for treating various diseases and disorders, for example, diseases in which ATF6-activated transcriptional targets play a role in the onset or development of the disease.For example, in some embodiments, the compound and composition can be used to treat viral infection, cancer, neurodegenerative disease, or vascular disease, for example, cardiovascular disease.In some embodiments, the disease is viral infection, hereditary cerebellar atrophy and ataxia, or Alzheimer's disease.In some embodiments, the disease is type 2 diabetes or diabetic nephropathy.In some embodiments, the disease is myocardial atrophy, heart failure, atherosclerosis, or ischemia, for example, ischemic heart disease or cerebral ischemia.

[0154] It has been demonstrated that the ATF6 branch of the UPR is central to viral infection. For example, ATF6 is important for maintaining cell survival and regulating immune responses during West Nile virus infection (Ambrose R J. Virol. February 2013 vol. 87 no. 4 2206-2214). African swine fever virus also activates the ATF6 branch to prevent early apoptosis and ensure viral replication (Galindo I, Cell Death Dis 2012 Jul 5;3:e341.doi:10.1038 / cddis.2012.81). Therefore, in some embodiments, the compounds or salts thereof described herein, or the compositions described herein, can be used in methods for treating or preventing viral infections. In some embodiments, the viral infection is an infection with African swine fever virus, dengue virus, enterovirus, hepatitis B virus, hepatitis C virus, influenza virus, tick-borne encephalitis virus, or West Nile virus. In some embodiments, the viral infection is caused by a virus that activates ATF6 in infected cells.

[0155] In some embodiments, the compounds or salts thereof described herein, or the compositions described herein, can be used in methods of treating cancer, such as breast cancer, colorectal cancer, ovarian cancer, prostate cancer, pancreatic cancer, kidney cancer, lung cancer, melanoma, fibrosarcoma, osteosarcoma, connective tissue sarcoma, renal cell carcinoma, giant cell carcinoma, squamous cell carcinoma, leukemia, skin cancer, soft tissue cancer, liver cancer, gastrointestinal cancer, or adenocarcinoma. In some embodiments, the compounds, salts, or compositions can be used in methods of treating metastatic kidney cancer, chronic lymphocytic leukemia, pancreatic adenocarcinoma, or non-small cell lung cancer.

[0156] ATF6α transcriptional targets are expressed at high levels in cancer cells.For example, there is a correlation between intracellular GRP78 levels and tumor size (Cai, JW, et al., J Cell Physiol, 1993,154(2):229-37).In addition, when GRP78 / BiP expression is experimentally suppressed in cancer cells and then injected into mice, the cells cannot form tumors due to increased sensitivity to cytotoxic T-cell (CTL) response and tumor necrosis factor (TNF) (Jamora, C., et al., Proc Natl Acad Sci USA, 1996,93(15):7690-7694; Sugawara, S., et al., Cancer Res, 1993,53(24):6001-6005).

[0157] Cellularly dormant cancer cells lack proliferative markers and exist in a quiescent state. Cells known to experience cellular dormancy include disseminated tumor cells (DTCs) and tumor cells located in the circulation (called circulating tumor cells (CTCs)) (Hensel, JA, et al., Nat Rev Clin Oncol, 2013, 10(1):41-51). Minimal residual disease caused by isolated DTCs is a well-recognized phenomenon associated with poor patient prognosis. DTCs, which typically stain negatively for proliferation markers (e.g., Ki67), can be a source of tumor recurrence, which can occur up to decades after treatment of the primary tumor (Meng, S., et al., Clin Cancer Res, 2004, 10(24):8152-8162). ATF6α has been reported to transmit survival signals through the ATF6α-Rheb-mTOR pathway for dormant cancer cells (Schewe, DM et al., Proc Natl Acad Sci USA, 2008, 105(30):10519-10524). ATF6α signaling is important for protection against ER and low glucose stress, and the interaction between ATF6α and mTOR signaling is thought to confer resistance to doxorubicin and the mTOR inhibitor rapamycin in dormant cancer cells, revealing a potential drug resistance mechanism (Schewe, DM et al., Proc Natl Acad Sci USA, 2008, 105(30):10519-10524).

[0158] In addition, multi-cancer studies have shown higher ATF6 expression in metastatic versus primary lesions, and colon cancer patients with increased expression of ATF6α in their primary tumors had a higher likelihood of recurrence (Ramaswamy, S., et al., Proc Natl Acad Sci USA, 2001, 98(26):15149-15154).

[0159] In some embodiments, the compound or salt thereof described herein, or the composition described herein, can be used in a method for treating cancer in an individual, and one or more cancer cells in the individual are dormant cancer cells.In some embodiments, one or more of the dormant cancer cells are disseminated tumor cells or circulating tumor cells.In some embodiments, one or more of the dormant cancer cells are disseminated tumor cells.

[0160] In some embodiments, the compounds or salts thereof described herein, or the compositions described herein, can be used in a method for treating cancer in an individual, wherein the individual has undergone prior treatment. In some embodiments, the cancer is resistant or refractory to prior treatment. In some embodiments, the cancer has progressed during prior treatment. In some embodiments, the cancer is a recurrent cancer. In some embodiments, the prior treatment was with a ubiquitin-proteasome pathway inhibitor (e.g., bortezomib), a taxane (e.g., paclitaxel or docetaxel), a Cox-2 inhibitor (e.g., celecoxib), a platinum-based anti-cancer drug (e.g., cisplatin or oxaliplatin), an anthracycline (e.g., doxorubicin), a pyrimidine analog (e.g., 5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide), an mTOR inhibitor (e.g., rapamycin), an immune checkpoint inhibitor, or an agent used in immuno-oncology. In some embodiments, the cancer is resistant to treatment with a ubiquitin-proteasome pathway inhibitor (e.g., bortezomib), a taxane (e.g., paclitaxel or docetaxel), a Cox-2 inhibitor (e.g., celecoxib), a platinum-based anti-cancer drug (e.g., cisplatin or oxaliplatin), an anthracycline (e.g., doxorubicin), a pyrimidine analog (e.g., 5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide), an mTOR inhibitor (e.g., rapamycin), an immune checkpoint inhibitor, or an agent used in immuno-oncology. In some embodiments, the cancer is resistant to treatment with doxorubicin and / or rapamycin.

[0161] In some embodiments, administration of the compound, salt, or composition reduces tumor growth, tumor proliferation, or tumorigenicity in an individual. In some embodiments, the compound, salt, or composition can be used in a method of reducing tumor growth, tumor proliferation, or tumorigenicity in an individual in need thereof. In some embodiments, tumor growth is slowed or stopped. In some embodiments, tumor growth is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, tumor size is reduced. In some embodiments, tumor size is reduced by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, tumor metastasis is prevented or slowed. In some embodiments, tumor growth, tumor proliferation, or tumorigenicity is compared to tumor growth, tumor proliferation, or tumorigenicity in the individual before administration of the compound, salt, or composition. In some embodiments, tumor growth, proliferation, or tumorigenicity is compared to tumor growth, proliferation, or tumorigenicity in similar individuals or populations. Methods of measuring tumor growth, proliferation, and tumorigenicity are known in the art, for example, by repeated imaging of individuals.

[0162] The compound or its salt is also believed to be effective in inhibiting angiogenesis. Activation of ATF6 and PERK contributes to the survival effect of vascular endothelial growth factor (VEGF) on endothelial cells (ECs) by positively regulating mTORC2-mediated phosphorylation of AKT on Ser473, which is required for full AKT activity. Reduction of PLCγ, ATF6, or eIF2a dramatically inhibited VEGF-induced angiogenesis in vivo in mouse Matrigel plugs, a standard angiogenesis assay (Karali, E. et al., Molecular Cell, 2014, 54:559-572). Therefore, the compound or its salt is believed to be effective in treating various diseases and disorders related to angiogenesis.

[0163] Angiogenesis is involved in the pathogenesis of a variety of diseases and disorders, including solid tumors and metastases, atherosclerosis, retrolental fibroplasia, hemangiomas, chronic inflammation, intraocular neovascular diseases such as proliferative retinopathies, e.g., diabetic retinopathy, age-related macular degeneration (AMD), neovascular glaucoma, immune rejection of transplanted corneal and other tissues, rheumatoid arthritis, and psoriasis. Thus, in some embodiments, the compounds and compositions are useful in treating cancer, e.g., any of the cancers described herein, unwanted or abnormal hypertrophy, arthritis, rheumatoid arthritis (RA), psoriasis, psoriatic plaques, sarcoidosis, atherosclerosis, atherosclerotic plaques, diabetic and other proliferative retinopathies including retinopathy of prematurity, retrolental fibroplasia, neovascular glaucoma, age-related macular degeneration, diabetic macular edema, corneal neovascularization, corneal graft neovascularization, corneal graft rejection, retinal / choroidal neovascularization, corneal neovascularization (rubeosis), ocular vascular diseases, vascular restenosis, arteriovenous malformations (AVMs), meningiomas, hemangiomas, angiofibromas, thyroid hyperplasia (including Graves' disease), corneal and other tissue transplants, chronic inflammation, pulmonary inflammation, acute lung injury / ARDS, sepsis, primary pulmonary hypertension, malignant lung diseases, and the like. Use in methods to treat effusions, cerebral edema (e.g., associated with acute stroke / closed head injury / trauma), synovitis, pannus formation in RA, myositis ossificans, heterotopic bone formation, osteoarthritis (OA), refractory ascites, polycystic ovarian disease, endometriosis, third space fluid disorders (pancreatitis, compartment syndrome, BUMS, bowel disorders), uterine fibroids, preterm labor, chronic inflammation such as IBD (Crohn's disease and ulcerative colitis), kidney allograft rejection, inflammatory bowel disease, nephrotic syndrome, unwanted or abnormal tissue mass growth (non-cancerous), hemophilic joints, hypertrophic scars, inhibition of hair growth, Osler-Weber syndrome, pyogenic granuloma, retrolental fibroplasia, scleroderma, trachoma, vascular adhesions, synovitis, dermatitis, preeclampsia, ascites, pericardial effusion (such as associated with pericarditis), and pleural effusion.

[0164] Breakdown in the intestinal barrier defense associated with microbial dysbiosis has emerged as a major contributing factor to several disorders, including inflammatory bowel disease, type 1 diabetes, Alzheimer's disease, and cancer. In particular, in patients with colorectal cancer (CRC), high expression levels of ATF6 in tumor tissues were associated with increased tumor size and reduced disease-free survival. Meanwhile, altered microbiota has been associated with CRC. These data demonstrate a link between UPR activation, microbiota, and colon tumorigenesis. A novel relationship between ATF6-mediated UPR activation and microbiota-dependent colon tumorigenesis has been demonstrated. Goblet cell loss and bacterial infiltration into epithelial crypts occurred prior to tumor formation, and antibiotic treatment of nATF6IEC mice significantly reduced tumor burden. In an inducible mouse model of ATF6 activation, there was a 100% tumor incidence rate at 26 weeks. Four days after induction of activated ATF6, there was a significant increase in bacterial proximity to the colonic epithelium along with increased cell proliferation, indicating that these changes are early events downstream of ATF6 activation. Some researchers found that microbial dysbiosis with reduced microbial diversity was present in the cecal contents of nATF6IEC mice, as assessed by 16S rRNA gene amplicon sequencing at 5 weeks of age, prior to the onset of tumor development. This dysbiotic microbiota enhanced tumor formation after transfer to germ-free nATF6IEC mice compared with transfer to control microbiota-containing nATF6IEC mice. These data indicate that microbial dysbiosis in the epithelium and subsequent STAT3 signaling significantly contribute to tumor development in this model.

[0165] Thus, in some embodiments, a compound or salt thereof described herein, or a composition described herein, can be used in a method for preventing or treating CRC through inhibition of ATF6, preventing goblet cell loss and dysbiosis. In some embodiments, a compound or salt thereof described herein, or a composition described herein, can be used in a method for blocking ATF6 signaling to antagonize tumor progression and reverse dysbiosis in a subset of CRC patients.

[0166] The ability of UPR signaling arms to distinctly influence ER proteostasis and function indicates that selective activation of these pathways has remarkable potential to alleviate pathological imbalances in ER proteostasis associated with etiologically diverse human diseases. In particular, activation of the ATF6 signaling arm has been shown to be useful for improving disease-related imbalances in ER proteostasis and function. Stress-independent activation of the ATF6 transcription factor using a chemical-genetic approach induces protective remodeling of ER proteostasis pathways and selectively reduces the secretion and extracellular aggregation of destabilized amyloid disease-associated proteins, such as transthyretin and immunoglobulin light chains, without significantly affecting the secretion of endogenous proteome (Shoulders et al., 2013; Chen et al., 2014; Cooley et al., 2014; Plate et al., 2016). Thus, the compounds described herein or salts thereof, or compositions described herein can be used in methods for correcting pathological imbalances in ER proteostasis in cell and animal models of protein misfolding and aggregation diseases.

[0167] One aspect of the present invention is based on the unexpected discovery that overexpression of ATF6 in a cell prevents cell death that would otherwise occur if unwanted accumulation of protein occurs in that cell. Thus, in some embodiments, the compounds or salts thereof described herein, or the compositions described herein, can be used in methods for treating conditions such as Parkinson's disease (PD), which are associated with the abnormal accumulation of molecules that interact with Parkin and are not properly disposed of in cells.

[0168] In some embodiments, the compounds or salts thereof described herein, or the compositions described herein, can be used in methods for preventing cell death. For example, it is contemplated within the present invention to prevent neuronal cell death, including the death of substantia nigra neurons in mammals, including humans.

[0169] In some embodiments, the compound or its salt described herein, or the composition described herein, can be used in methods for treating neurodegenerative diseases associated with abnormal protein precipitation and / or aggregation.For example, the brains of patients with Alzheimer's disease show neurofibrillary tangles (NFTs), senile plaques, and cerebrovascular deposits of amyloid beta; the brains of patients with prion disease show plaques containing prion protein; the brains of patients with Huntington's disease show huntingtin deposits; patients with dominantly inherited spinocerebellar ataxia show corresponding ataxin protein deposits; patients with multiple system atrophy show alpha-synuclein deposits; patients with progressive supranuclear palsy show tau deposits; and patients with familial amyotrophic lateral sclerosis show SOD1 deposits (Johnson, WG, J.Anat.4:609-616(2000)). Because these various diseases share common pathological mechanisms, they may share pathways that lead to abnormal aggregation and / or precipitation of proteins (Hardy, J. and Gwinn-Hardy, K., Science 282(5391):1075-1079(1998)).

[0170] In some embodiments, the compound or its salt described herein, or the composition described herein, can be used as a monotherapy or in combination with other palliative drugs (e.g., drugs that alleviate the symptoms of the disorder being treated) and / or drugs that target the cause of the disorder.For example, the composition that increases the expression of ATF6 can be administered to a subject together with the administration of L-DOPA, dopamine agonist, monoamine oxidase B inhibitor, or any other composition that is useful in the treatment of neurodegenerative diseases such as Parkinson's disease.

[0171] Overexpression of active ATF6 transcription factor in the heart has also been shown to improve cardiac function in a mouse model of ischemic heart disease through a mechanism involving ATF6-dependent regulation of the antioxidant gene, catalase (Jin et al., 2017). Similarly, overexpression of active ATF6 transcription factor in the liver improves insulin sensitivity in obese mice (Ozcan et al., 2016). These results indicate that ATF6 activation offers a unique therapeutic opportunity to improve ER proteostasis defects implicated in various diseases.

[0172] In some embodiments, the compounds or salts thereof described herein, or the compositions described herein, can be used in methods for improving myocardial recovery from I / R injury, particularly by activating the endogenous adaptive ATF6 gene program in the heart.

[0173] The ATF6α pathway also plays a role in stress-induced lipid accumulation. p50ATF6 interacts with the nuclear form of SREBP-2, thereby antagonizing SREBP-2-regulated transcription of lipogenic genes and lipid accumulation in cultured hepatocytes and kidney cells. Furthermore, Atf6α-deficient mice exhibited significantly longer liver dysfunction and steatosis than wild-type mice in response to pharmacological induction of ER stress. This could be explained by chronic expression of CHOP and sustained suppression of C / EBPα, and / or a failure of ATF6α-mediated induction of genes encoding protein chaperones, transport, and ERAD functions. During feeding, HFD, and Atf6α - / - Mice developed hepatic steatosis and glucose intolerance associated with increased expression of SREBP-1c, whereas overexpression of a functionally active nuclear fragment of ATF6 in zebrafish led to hepatic steatosis, indicating that fine-tuning of ATF6α may be important for preventing hepatic steatosis.

[0174] In some embodiments, the compounds or salts thereof described herein, or the compositions described herein, may be used in methods to treat metabolic disorders such as obesity, type I and type II diabetes, pancreatitis, dyslipidemia, hyperlipidemic conditions, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), insulin resistance, hyperinsulinemia, glucose intolerance, hyperglycemia, metabolic syndrome, acute myocardial infarction, hypertension, cardiovascular disease, atherosclerosis, peripheral artery disease, stroke, heart failure, coronary heart disease, kidney disease, diabetic complications, neuropathy, gastroparesis, disorders associated with severe inactivating mutations in the insulin receptor, and other metabolic disorders.

[0175] In some embodiments, the compounds or salts thereof described herein, or the compositions described herein, can be used in methods for treating ischemic heart disease or myocardial recovery from ischemia / reperfusion (I / R).

[0176] In accordance with the present disclosure, in some embodiments, the individual is a mammal. In some embodiments, the individual is a primate, cow, sheep, pig, horse, dog, cat, rabbit, or rodent. In some embodiments, the individual is a human. In some embodiments, the individual has any of the diseases or disorders disclosed herein. In some embodiments, the individual is at risk of developing any of the diseases or disorders disclosed herein.

[0177] Also provided herein is the use of the compound described herein or its pharmaceutically acceptable salt, or the pharmaceutical composition described herein, in the manufacture of a medicament.In some embodiments, the manufacture of the medicament is for the treatment of the disorder or disease described herein.In some embodiments, the manufacture of the medicament is for the prevention and / or treatment of the disorder or disease mediated by ATF6 pathway, ATF6, or ATF6α.

[0178] Combination therapy As provided herein, the compounds described herein or salts thereof, and the compositions described herein, can be administered together with drugs to treat any of the diseases and disorders disclosed herein. In some embodiments, the drug modulates the unfolded protein response or the integrated stress response. In some embodiments, the drug is an anti-angiogenic agent. In some embodiments, the drug is an anti-cancer agent. In some embodiments, the drug targets an immune checkpoint protein.

[0179] In some embodiments, (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, and (b) a drug are administered sequentially, in combination, or simultaneously. In certain embodiments, (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, and (b) a drug are administered at a time separation of about 15 minutes or less, for example, about 10, 5, or 1 minute or less. In certain embodiments, (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, and (b) a drug are administered at a time separation of about 15 minutes or more, for example, about 20, 30, 40, 50, 60 minutes, or more. (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, and (b) a drug may be administered first. In certain embodiments, (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, and (b) the agent are administered simultaneously.

[0180] In some embodiments, the agent modulates the unfolded protein response or the integrated stress response. In some embodiments, the agent inhibits the unfolded protein response or the integrated stress response. In some embodiments, the agent modulates the PERK pathway. In some embodiments, the agent inhibits the PERK pathway. In some embodiments, the agent inhibits PERK. ATF6 is known to act in conjunction with IRE1, and as one of the target genes of ATF6, XBP1 is a major substrate of IRE1 (Yoshida, H., et al., Cell, 2001, 107(7):881-891). For example, ATF6 and IRE1 signaling are important for the survival of melanoma cells subjected to ER stress, indicating the potential benefit of using an ATF6 inhibitor in combination with an IRE1 inhibitor (Tay, KH, et al., Cell Signal, 2014, 26(2):287-294). Thus, in some embodiments, the agent modulates the IRE1 / XBP1 pathway. In some embodiments, the agent inhibits the IRE1 / XBP1 pathway. In some embodiments, the agent inhibits IRE1 or XBP1.

[0181] In some embodiments, the agent is an anti-angiogenic agent. The compound or its salt is believed to be effective for inhibiting angiogenesis and treating angiogenesis-related diseases and disorders. Thus, provided herein is a method for inhibiting angiogenesis, comprising administering to an individual (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, and (b) an anti-angiogenic agent. Also provided herein is a method for treating angiogenesis-related diseases or disorders, such as any angiogenesis-related disease or disorder disclosed herein, comprising administering to an individual (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, and (b) an anti-angiogenic agent. In some embodiments, the anti-angiogenic agent is a VEGF antagonist. In some embodiments, the anti-angiogenic agent is bevacizumab or ranibizumab.

[0182] The role of angiogenesis as a mediator of immune regulation in the tumor microenvironment has recently gained attention. Furthermore, new evidence indicates that immunotherapy can result in immune-mediated vascular damage in tumors, suggesting that the tumor vasculature may be a critical interface between the tumor-directed immune response and the cancer itself. The introduction of immune checkpoint inhibition as an effective immunotherapeutic strategy for many cancers has led to a better understanding of this interface. Initial studies of the complex relationship between angiogenesis, VEGF signaling, and the immune system suggest that combining immune checkpoint blockade with angiogenesis inhibition has potential, and efforts to improve immunotherapy will have far-reaching impact on the future of oncology. The effect of ATF6 on VEGF signaling reinforces the idea of ​​using ATF6 inhibitors in combination with immune checkpoint inhibitors (Ott, PA, FS Hodi, and EI Buchbinder, Inhibition of Immune Checkpoints and Vascular Endothelial Growth Factor as Combination Therapy for Metastatic Melanoma: An Overview of Rationale, Preclinical Evidence, and Initial Clinical Data. Front Oncol, 2015. 5: p. 202).

[0183] Thus, in some embodiments, the agent targets an immune checkpoint protein. In some embodiments, the agent is an antibody that targets an immune checkpoint protein. In some embodiments, the agent targets PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, CCR4, OX40, OX40L, IDO, and A2AR. In some embodiments, the agent is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0184] Provided herein are methods for enhancing an immune response in an individual, comprising administering to the individual (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, and (b) an agent that targets an immune checkpoint protein. In some embodiments, the individual has cancer. In some embodiments, the enhanced immune response is directed against tumors or cancer cells.

[0185] Also provided herein is a method of treating cancer in an individual in need thereof, comprising administering to the individual (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, and (b) an agent that targets an immune checkpoint protein, wherein the individual's immune response is increased.

[0186] In some embodiments, the agent is an anti-cancer agent. In some embodiments, the anti-cancer agent is a ubiquitin-proteasome pathway inhibitor (e.g., bortezomib), a taxane (e.g., paclitaxel or docetaxel), a Cox-2 inhibitor (e.g., celecoxib), a platinum-based anti-neoplastic agent (e.g., cisplatin or oxaliplatin), an anthracycline (e.g., doxorubicin), a pyrimidine analog (e.g., 5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide), or an agent that modulates the unfolded protein response or integrated stress response (e.g., an IRE1 / XBP1 inhibitor or a PERK inhibitor). In some embodiments, the anti-cancer agent is oxaliplatin, 5-fluorouracil, or gemcitabine. In some embodiments, the anti-cancer agent is an immune checkpoint inhibitor or an agent used in immuno-oncology.

[0187] In some embodiments, an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein is administered to an individual with cancer to increase sensitivity to one or more anti-cancer treatments.

[0188] Therapeutic resistance is a major barrier to improving outcomes for cancer patients. Radiation can induce ER stress and its downstream signaling, which is thought to be related to changes in ROS balance secondary to irradiation. Previously, knockdown of ATF6 was sufficient to improve radiation-induced cell death (Dadey, DY, et al., Oncotarget, 2016, 7(2):2080-2092). This indicates ATF6 as a potential therapeutic target for improving the efficacy of radiation therapy.

[0189] In some embodiments, an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, is administered to an individual having cancer to increase sensitivity to radiation. In some embodiments, provided herein are methods for treating cancer in an individual in need thereof, comprising administering to the individual (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, and (b) radiation.

[0190] In some embodiments, an effective amount of the compound described herein, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described herein, is administered to an individual with cancer to increase sensitivity to one or more anti-cancer agents. In some embodiments, the anti-cancer agent is a ubiquitin-proteasome pathway inhibitor (e.g., bortezomib), a taxane (e.g., paclitaxel or docetaxel), a Cox-2 inhibitor (e.g., celecoxib), a platinum-based anti-neoplastic agent (e.g., cisplatin or oxaliplatin), an anthracycline (e.g., doxorubicin), a pyrimidine analog (e.g., 5-fluorouracil or gemcitabine), a topoisomerase inhibitor (e.g., etoposide), or an agent that modulates unfolded protein response or integrated stress response (e.g., IRE1 / XBP1 inhibitor or PERK inhibitor). In some embodiments, the anti-cancer agent is oxaliplatin, 5-fluorouracil, or gemcitabine. In some embodiments, the anti-cancer agent is an immune checkpoint inhibitor or an agent used in immuno-oncology.

[0191] Provided herein are methods for treating metabolic and / or fibrotic diseases in individuals, comprising administering to the individual (a) a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, and (b) a drug. In some embodiments, the drug is a proteasome inhibitor, such as bortezomib, carfilzomib, and ixazomib. In some embodiments, the drug is a monoclonal antibody, such as daratumumab and elotuzumab. In some embodiments, the drug is an inhibitor of histone deacetylase (HDAC) proteins, such as panobinostat, romidepsin, and vorinostat. In some embodiments, the drug is an immunomodulatory drug (IMiD), such as thalidomide, lenalidomide, and pomalidomide. In some embodiments, the drug is a corticosteroid, such as dexamethasone, prednisone, prednisolone, and methylprednisolone. In some embodiments, the agent is a therapy that targets IRE1-XBP1.

[0192] Administration and Method of Administration The dose of the compound administered to an individual (such as a human) can vary with the particular compound or salt thereof, the method of administration, and the particular disease, such as the type and stage of cancer being treated. In some embodiments, the amount of the compound or salt thereof is a therapeutically effective amount.

[0193] In one embodiment, an effective amount of the compound may be a dose of about 0.01 to about 100 mg / kg. The effective amount or dose of the compound of the present invention may be confirmed by routine methods such as modeling, dose escalation, or clinical trials, taking into account factors such as the mode or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the disease being treated, and the subject's health, condition, and body weight. An exemplary dose ranges from about 0.1 mg to 10 g daily.

[0194] Any of the methods provided herein can, in one aspect, include administering to an individual a pharmaceutical composition comprising an effective amount of a compound provided herein, or a salt thereof, and a pharmaceutically acceptable excipient.

[0195] The compounds or compositions of the present invention may be administered to an individual according to an effective dosing regimen for a desired period or duration, for example, at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more, which in some variations may be the duration of the individual's life. In one variation, the compound is administered on a daily schedule or an intermittent schedule. The compound can be administered to an individual continuously (e.g., at least once daily) for a period of time. The dosing frequency can also be less than once daily, for example, about once a week. The dosing frequency can also be more than once daily, for example, twice or three times daily. The dosing frequency can also be intermittent, including "drug holidays" (e.g., once daily for 7 days, followed by 14-day periods without 7 days of dosing, repeated for any period of about 2 months, about 4 months, about 6 months, or more). Any of the dosing frequencies can be used with any of the compounds described herein and any of the doses described herein.

[0196] The compounds provided herein or their salts can be administered to individuals via various routes, including, for example, intravenous, intramuscular, subcutaneous, oral, and transdermal. In some embodiments, the compounds or compositions are administered orally. The compounds provided herein can be administered at low doses frequently, known as "metronomic therapy," or as part of a maintenance therapy, in which the compounds are used alone or in combination with one or more additional drugs. Metronomic therapy or maintenance therapy can include the administration of the compounds provided herein in cycles. Metronomic therapy or maintenance therapy can include the intratumoral administration of the compounds provided herein.

[0197] Also provided herein are compositions (including pharmaceutical compositions) described herein for use in treating, preventing, and / or delaying the onset and / or progression of the diseases described herein, and other methods described herein. In certain embodiments, the compositions comprise pharmaceutical formulations present in unit dosage form.

[0198] Products and Kits The present disclosure further provides a product that includes the compound or its salt of the present disclosure, composition, and the unit dose described herein in suitable packaging.In certain embodiments, the product is for use in any of the methods described herein.Suitable packaging is known in the art, and includes, for example, vial, container, ampoule, bottle, jar, flexible packaging, and the like.The product can also be sterilized and / or sealed.

[0199] The present disclosure further provides a kit for carrying out the method of the present disclosure, comprising one or more compounds described herein or a composition comprising a compound described herein.The kit may use any of the compounds disclosed herein.In one variation, the kit uses a compound described herein or a pharmaceutically acceptable salt thereof.The kit may be used for any one or more of the uses described herein, and therefore may include instructions for treating the diseases described herein, such as cancer.

[0200] Kit generally includes suitable packaging.Kit may include one or more containers that contain any compound described herein.Each component (if there is more than one component) can be packaged in separate containers, or some components can be combined in one container that allows cross-reactivity and shelf life.

[0201] The kit can be a unit dosage form, bulk package (e.g., multi-dose package) or sub-unit dose. For example, a kit can be provided that contains a sufficient dose of the compound disclosed herein and / or a second pharmaceutically active compound useful for the diseases detailed herein (e.g., hypertension) to provide effective treatment for an individual for a long period of time, such as 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. The kit can also include multiple unit doses of the compound and instructions for use, and can be packaged in an amount sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0202] The kit may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskettes or optical disks) containing instructions are also acceptable relating to the use of the component(s) of the methods of the invention. The instructions included in the kit generally include information regarding the components and their administration to an individual.

[0203] The present invention can be further understood by reference to the following examples, which are provided by way of illustration and are not meant to be limiting. [Example]

[0204] Synthesis Examples The following examples are provided to illustrate, but not to limit, the present disclosure. Those skilled in the art will recognize that the following synthetic reactions and schemes can be modified by selecting appropriate starting materials and reagents to access other compounds of formula (I), or salts thereof. The compounds are prepared using the general methods described above.

[0205] The following abbreviations are used throughout the examples: DCM (dichloromethane), DIAD (diisopropyl azodicarboxylate), DIPEA or DIEA (N,N-diisopropylethylamine), DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), HATU ((1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate), HPLC (high pressure liquid chromatography), IPA (isopropyl alcohol), LCMS (liquid chromatography mass spectrometry), NMR (nuclear magnetic resonance), PPh3 (triphenylphosphane), RT (room temperature), TEA (triethylamine), THF (tetrahydrofuran), and TLC (thin layer chromatography).

[0206] Example S1 Example S1-1. Synthesis of N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (compound 1-1).

[0207] [ka] Step 1: Synthesis of 1-(2,6-dichlorophenyl)ethan-1-ol. To a stirred solution of 1-(2,6-dichlorophenyl)ethan-1-one (1 gm, 5.28 mmol, 1.0 equiv) in methanol (5 mL), NaBH (303 mg, 8.0 mmol, 1.5 equiv) was added portionwise at 0 °C and stirred for 10 minutes. The reaction mixture was allowed to stir at room temperature for 1 hour. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (50 mL × 3). The combined organic extracts were washed with water (50 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure to give 1-(2,6-dichlorophenyl)ethan-1-ol (990 mg as a colorless liquid). 1H NMR (400 MHz, DMSO-d6) δ 7.47 - 7.63 (m, 2H), 7.30 - 7.47 (m, 1H), 5.55 (br. s., 1H), 4.20 (br. s., 1H), 1.45 (d, J = 6.58 Hz, 3H).

[0208] Step 2: Synthesis of 1-(1-(2,6-dichlorophenyl)ethyl)-4-nitro-1H-pyrazole. To a stirred solution of PPh3 (413 mg, 1.578 mmol, 1.5 equiv) and DIAD (318.94 mg, 1.578 mmol, 1.5 equiv) in THF (2 mL), 4-nitro-1H-pyrazole (118.947 mg, 1.05 mmol, 1 equiv) was added, followed by 1-(2,6-dichlorophenyl)ethan-1-ol (200 mg, 1.05 mmol, 1.0 equiv). The resulting reaction mixture was stirred at room temperature for 1 h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the mixture was diluted with EtOAc (50 mL) and washed with water (50 mL × 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was further purified by flash column chromatography to give the pure product 1-(1-(2,6-dichlorophenyl)ethyl)-4-nitro-1H-pyrazole (160 mg). 1 H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.27 (s, 1H), 7.49 (d, J = 7.89 Hz, 2H), 7.29 - 7.44 (m, 1H), 6.13 - 6.36 (m, 1H), 1.99 (d, J = 7.02 Hz, 3H).

[0209] Step 3: Synthesis of 1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-amine. To a stirred solution of 1-(1-(2,6-dichlorophenyl)ethyl)-4-nitro-1H-pyrazole (160 mg, 0.6235 mmol, 1 equiv.) in 10 mL of EtOH / water (1:1), Fe (172.5 mg, 3.135 mmol, 5 equiv.) and ammonium chloride (175.68 mg, 3.136 mmol, 5 equiv.) were added and heated at 80° C. for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a Celite pad, and the filtrate was evaporated and extracted twice with DCM / water. The organic layer was collected and evaporated under reduced pressure to give 1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-amine (110 mg). LCMS: 256 [M+H] + .

[0210] Step 4: Synthesis of 1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride. To a stirred solution of 1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-amine (100 mg) in ethanol, HCl in ethanol (1 mL) was added and allowed to stir at room temperature for 1 hour. After completion of the reaction, the reaction mixture was evaporated and lyophilized to give the product 1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride (125 mg). LCMS: 256 [M+H] + .

[0211] Step 5: Synthesis of N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. To a solution of 5-(furan-2-yl)isoxazole-3-carboxylic acid (50 mg, 0.277 mmol, 1 equiv.) in DMF (1 mL) was added HATU (105.5 mg, 0.277 mmol, 1.0 equiv.). The mixture was treated dropwise with DIPEA (107.99 ml, 0.831 mmol, 3.0 equiv.). After stirring at room temperature for 15 minutes, the mixture was treated dropwise with a solution of 1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride (80.55 mg, 0.555 mmol, 1 equiv.) in DMF (1 mL). The reaction mixture was kept under stirring for 24 hours. After completion of the reaction, the mixture was diluted with EtOAc (50 mL) and washed with water (10 mL x 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was further purified by trituration with acetone-hexane (8:2) ml to give the precipitate as N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. LCMS: 417 [M+H] + .

[0212] Step 6: Synthesis of (R) and (S)—N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. The racemic mixture of N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide was purified by chiral normal-phase HPLC (Daicel Chiralpak®-IC, 250 × 20 mm, 5 μm). An isocratic program with HPLC-grade n-hexane and HPLC-grade isopropanol, total flow rate: 56 ml / min, cosolvent percentage: 10%, gave Enantiomer A (12 mg) and Enantiomer B (10 mg). LCMS 417 [M+H] + ; Enantiomer A, 1H NMR (400 MHz, DMSO-d6) δ ppm 11.03 (br. s., 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.64 (s, 1H), 7.49 (d, J = 7.89 Hz, 2H), 7.34 - 7.41 (m, Enantiomer B, 1 H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.11 (s, 1H), 8.01 (s, 1H), 7.66 (s, 1H), 7.49 (d, J = 7.89 Hz, 2H), 7.34 - 7.41 (m, 1H), 7.29 (d, J = 3.95 Hz, 1H), 7.14 (s, 1H), 6.78 (br. s., 1H), 6.10-6.21 (m, 1H), 1.96 (d, J = 7.45 Hz, 3H).

[0213] Example S1-2. Synthesis of N-(1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (compound 1-2).

[0214] [ka] Step 1: Synthesis of 5-chloro-2,3-dihydro-1H-inden-1-ol. To a stirred solution of 5-chloro-2,3-dihydro-1H-inden-1-one (500 mg, 3.01 mmol, 1.0 equivalent (eq)) in methanol (20 mL) was added NaBH (120 mg, 4.518 mmol, 1.5 eq) in portions at 0 °C and stirred for 10 minutes. The reaction mixture was allowed to stir at room temperature for 1 hour. Product formation was confirmed by TLC and NMR. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with water (2 × 50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 5-chloro-2,3-dihydro-1H-inden-1-ol (500 mg).

[0215] Step 2: Synthesis of 1-bromo-5-chloro-2,3-dihydro-1H-indene. To a stirred solution of 5-chloro-2,3-dihydro-1H-inden-1-ol (500 mg, 2.747 mmol, 1 equiv.) in DCM (10 mL), PBr3 (893 mg, 3.29 mmol, 1.2 equiv.) was added portionwise at 0 °C. The reaction mixture was then stirred at room temperature for 2 h. Product formation was monitored by TLC and 1 After completion of the reaction, the mixture was diluted with EtOAc (50 mL) and washed with water (50 mL×3), and the organic layer was dried over NaSO and concentrated under reduced pressure to give the crude product, which was further purified by flash column chromatography to give the pure product 1-bromo-5-chloro-2,3-dihydro-1H-indenepyrazole (702 mg as a brown liquid).

[0216] Step 3: Synthesis of 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-4-nitro-1H-pyrazole. To a solution of 4-nitro-1H-pyrazole (300 mg, 1.304 mmol, 1 equiv.) in DMF (1 mL) was added KCO (270 mg, 1.955 mmol, 1.5 equiv.) at 0 °C. After stirring for 15 min, the mixture was treated dropwise with a solution of 1-bromo-5-chloro-2,3-dihydro-1H-indene (147 mg, 1.304 mmol, 1 equiv.) in DMF (1 mL). The reaction mixture was kept under stirring for 24 h. Product formation was confirmed by TLC and LCMS, and the reaction mixture was diluted with EtOAc (50 mL), washed with water (2 × 50 mL), and the organic layer was dried over NaSO and concentrated under reduced pressure to give the crude product, which was further purified by flash column chromatography to give pure 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-4-nitro-1H-pyrazole (225 mg as a white solid). 1 H NMR (400 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.27 (s, 1H), 7.43 (s, 1H), 7.25 (d, J = 8.77 Hz, 1H), 7.17 (d, J = 8.33 Hz, 1H), 5.92 - 6.03 (m, 1H), 3.14 - 3.24 (m, 1H), 2.90 - 3.04 (m, 1H), 2.62 - 2.73 (m, 2H), 2.41 - 2.48 (m, 1H).

[0217] Step 4: Synthesis of 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine. To a stirred solution of 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-4-nitro-1H-pyrazole (150 mg, 0.566 mmol, 1 equiv.) in 10 mL of EtOH / water (1:1), Fe (155.66 mg, 2.83 mmol, 5 equiv.) and ammonium chloride (158 mg, 2.83 mmol, 5 equiv.) were added and heated at 80° C. for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite pad, the filtrate was evaporated and extracted with DCM (100 ml x 2), the organic layer was collected and evaporated under reduced pressure to give 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine (180 mg). LCMS: 234 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 7.38 (s, 1H), 7.21 (d, J = 6.14 Hz, 1H), 7.02 (d, J = 8.33 Hz, 1H), 6.97 (s, 1H), 6.93 (s, 1H), 5.62 - 5.70 (m, 1H), 3.85 (br. s., 2H), 3.02 - 3.13 (m, 1H), 2.83 - 2.96 (m, 1H), ).

[0218] Step 5: Synthesis of 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine hydrochloride. To a stirred solution of 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine (180 mg) in ethanol (1 mL), 4M HCl in ethanol (2 ml) was added at room temperature for 2 hours. Product formation was monitored by TLC and 1 The reaction mixture was concentrated under reduced pressure to give the crude product, which was further triturated with diethyl ether and lyophilized to give the pure product 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine hydrochloride (150 mg, brown solid). 1H NMR (400 MHz, DMSO-d6) δ 10.07 (br. s., 2H), 8.01 (s, 1H), 7.56 (s, 1H), 7.43 (s, 1H), 7.25 (d, J = 8.33 Hz, 1H), 7.05 (d, J = 8.33 Hz, 1H), 5.87 - 6.01 (m, 1H), 3.07 - 3.19 (m, 1H), 2.95 (td, J = 7.73, 15.68 Hz, 1H), 2.63 (dtd, J = 5.26, 8.17, 13.48 Hz, 1H), 2.28 - 2.43 (m, 2H).

[0219] Step 6: Synthesis of N-(1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. To a solution of 5-(furan-2-yl)isoxazole-3-carboxylic acid (50 mg, 0.277 mmol, 1 equiv.) in DMF (1 mL) was added HATU (105.8 mg, 0.277 mmol, 1 equiv.). The mixture was treated dropwise with DIPEA (107.5 mg, 0.833 mmol, 3 equiv.). After stirring at room temperature for 15 minutes, the mixture was treated dropwise with a solution of 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine hydrochloride (64.722 mg, 0.277 mmol, 1 equiv.) in DMF (1 mL). The reaction mixture was kept stirring for 24 hours. Product formation was confirmed by TLC and LCMS, and the reaction mixture was diluted with EtOAc (50 mL), washed with water (2×50 mL), and the organic layer was dried over NaSO and concentrated under reduced pressure to give the crude product, which was further purified by flash column chromatography to give pure N-(1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (50 mg as a white solid). LCMS: 395 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.66 (s, 1H), 7.42 (s, 1H), 7.28 (d, J = 3.07 Hz, 1H), 7.24 (d, J = 7.89 Hz, 1H), 7.14 (s, 1H), 7.07 (d, J = 7.89 Hz, 1H), 6.77 (dd, J = 1.75, 3.51 Hz, 1H), 5.84 - 5.94 (m, 1H), 3.04 - 3.20 (m, H1), 2.94 (td, J = 7.67, 15.35 Hz, 1H), 2.56 - 2.70 (m, 1H), 2.28 - 2.42 (m, 1H).

[0220] Step 7: Separation of N-(1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide isomers. The enantiomers of N-(1-(1-(5-chloro-2,3-dihydro-1H-inden-1-yl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (50 mg, elution times 14.12 and 15.87 min) were separated by chiral SFC (Daicel Chiralpak-IC 250 × 20 mm, 5 μm). An isocratic program using analytical grade liquid carbon dioxide and HPLC grade methanol, total flow rate: 4 g / min, co-solvent percentage: 40%, resulted in the first eluting enantiomer, Enantiomer A (8 mg), LCMS: 395 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.66 (s, 1H), 7.42 (s, 1H), 7.28 (d, J = 3.07 Hz, 1H), 7.24 (d, J = 7.89 Hz, 1H), 7.14 (s, 1H), 7.07 (d, J = 7.89 Hz, 1H), 6.77 (dd, J = 1.75, 3.51 Hz, 1H), 5.84 - 5.94 (m, 1H), 3.04 - 3.20 (m, 1H), 2.94 (td, J = 7.67, 15.35 Hz, 1H), 2.56 - 2.70 (m, 1H), 2.28 - 2.42 (m, 1H) and the second eluting enantiomer, Enantiomer B (8 mg), LCMS: 395 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.66 (s, 1H), 7.43 (s, 1H), 7.28 (d, J = 3.07 Hz, 1H), 7.24 (d, J = 10.09 Hz, 1H), 7.14 (s, 1H), 7.07 (d, J = 7.89 Hz, 1H), 6.77 (dd, J = 1.75, 3.51 Hz, 1H), 5.88 - 5.94 (m, 1H), 3.07 - 3.20 (m, 1H), 2.94 (td, J = 7.73, 15.68 Hz, 1H), 2.55 - 2.69 (m, 1H), 2.29 - 2.44 (m, 1H).

[0221] Example S1-3. Synthesis of 5-(furan-2-yl)-N-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide (compound 1-3).

[0222] [ka] Step 1: Synthesis of 1,2,3,4-tetrahydronaphthalen-1-ol. To a stirred solution of 3,4-dihydronaphthalen-1(2H)-one (500 mg, 3.4 mmol, 1.0 equiv.) in methanol (20 mL), NaBH (120 mg, 5.1 mmol, 1.5 equiv.) was added portionwise at 0 °C and stirred for 10 minutes. The reaction mixture was allowed to stir at room temperature for 1 hour. Product formation was confirmed by TLC and NMR. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with water (2 × 50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give 1,2,3,4-tetrahydronaphthalen-1-ol (500 mg).

[0223] Step 2: Synthesis of 1-bromo-1,2,3,4-tetrahydronaphthalene. To a stirred solution of 1,2,3,4-tetrahydronaphthalen-1-ol (500 mg, 3.37 mmol, 1 equiv.) in DCM (10 mL) was added PBr3 (1098 mg, 4.05 mmol, 1.2 equiv.) dropwise at 0 °C. The reaction mixture was then stirred at room temperature for 2 h. Product formation was monitored by TLC and 1 The reaction mixture was confirmed by HNMR. After completion of the reaction, the mixture was diluted with EtOAc (50 mL) and washed with water (50 mL × 3). The organic layer was dried over NaSO and concentrated under reduced pressure to give the crude product, which was further purified by flash column chromatography to give pure 1-bromo-1,2,3,4-tetrahydronaphthalene (632 mg, crude as a brown liquid). 1 H NMR (400 MHz, DMSO-d6): δ 8.61 (d, J = 5.26 Hz, 1H), 8.15 (d, J = 7.45 Hz, 2H), 7.50 - 7.63 (m, 1H), 5.88 (d, J = 4.38 Hz, 1H), , 3.18 - 3.34 (m, 2H), 3.01 - 3.15 (m, 2H), 2.76 (td, J = 7.56, 14.69 Hz, 2H)

[0224] Step 3: Synthesis of 4-nitro-1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazole. To a solution of 4-nitro-1H-pyrazole (161.4 mg, 1.428 mmol, 1 equiv.) in DMF (1 mL) was added K2CO3 (295.71 mg, 2.14 mmol, 1.5 equiv.) at 0 °C. After stirring for 15 min, the mixture was treated dropwise with a solution of 1-bromo-1,2,3,4-tetrahydronaphthalene (300 mg, 1.428 mmol, 1 equiv.) in DMF (1 mL). The reaction mixture was kept stirring for 24 h. Product formation was confirmed by TLC and LCMS, and the reaction mixture was diluted with EtOAc (50 mL) and washed with water (2 × 50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude material, which was further purified by flash column chromatography to give pure 4-nitro-1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazole (250 mg as a white solid). 1 H NMR (400 MHz, DMSO-d6): 1 H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.26 (s, 1H), 7.26 - 7.41 (m, 2H), 7.11 - 7.26 (m, 2H), 5.93 - 6.06 (m, 1H), 3.07 - 3.20 (m, 1H), 2.90 - 3.03 (m, 1H), 2.60 - 2.71 (m, 2H), 2.40 - 2.48 (m, 2H).

[0225] Step 4: Synthesis of 1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-amine. To a stirred solution of 4-nitro-1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazole (150 mg, 0.617 mmol, 1 equiv.) in 10 mL of EtOH / water (1:1), Fe (169.7 mg, 3.085 mmol, 5 equiv.) and ammonium chloride (172 mg, 3.085 mmol, 5 equiv.) were added and heated at 80° C. for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a celite pad, the filtrate was evaporated and extracted with DCM (100 ml × 2), the organic layer was collected and evaporated under reduced pressure to give 1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-amine (121 mg). LCMS: 214 [M+H] + , 1 H NMR (400 MHz, DMSO-d6): 1 H NMR (400 MHz, DMSO-d6) δ7.38 (s, 1H), 7.16 - 7.28 (m, 1H), 6.92 - 7.07 (m, 4H), 5.57 - 5.74 (m, 1H), 3.90 - 3.82 (br, 2H), 2.89 - 3.10 (m, 2H), 2.83 - 2.89 (m, 2H), 2.25 - 2.39 (m, 2H).

[0226] Step 5: Synthesis of 1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-amine hydrochloride. To a solution of 1-(5-chloro-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine (120 mg) in ethanol (1 mL) was added 4M HCl in ethanol (2 ml). Product formation was monitored by TLC and 1 The reaction mixture was concentrated under reduced pressure to give the crude product, which was further triturated with diethyl ether and lyophilized to give the pure product 1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-amine hydrochloride (123 mg, brown solid). 1H NMR (400 MHz, DMSO-d6): δ 10.16 (br. s., 2H), 7.81 (s, 1H), 7.58 (s, 1H), 7.14 - 7.27 (m, 2H), 7.11 (t, J = 7.24 Hz, 1H), 6.73 (d, J = 7.89 Hz, 1H), 5.63 (t, J = 6.58 Hz, 1H), 2.69 - 2.94 (m, 2H), 2.10 - 2.26 (m, 2H), 1.71 - 1.91 (m, 2H).

[0227] Step 6: Synthesis of 5-(furan-2-yl)-N-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide. To a solution of 5-(furan-2-yl)isoxazole-3-carboxylic acid (50 mg, 0.277 mmol, 1 equiv.) in DMF (1 mL) was added HATU (105.8 mg, 0.277 mmol, 1 equiv.). The mixture was treated dropwise with DIPEA (107.5 mg, 0.833 mmol, 3 equiv.). After stirring at room temperature for 15 minutes, the mixture was treated dropwise with a solution of 1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-amine hydrochloride (68.88 mg, 0.277 mmol, 1 equiv.) in DMF (1 mL). The reaction mixture was kept under stirring for 24 hours. Product formation was confirmed by TLC and LCMS, and the reaction mixture was diluted with EtOAc (50 mL) and washed with water (2 x 50 mL). The organic layer was dried over NaSO and concentrated under reduced pressure to give the crude product, which was further purified by flash column chromatography to give pure 5-(furan-2-yl)-N-(1-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide (40 mg, 42.59%) as a white solid. LCMS: 375 [M+H] + , 1H NMR (400 MHz, DMSO-d6): δ 11.00 (s, 1H), 8.00 (s, 1H), 7.89 (s, 1H), 7.69 (s, 1H), 7.23 - 7.32 (m, 1H), 7.15 - 7.23 (m, 2H), 7.04 - 7.15 (m, 2H), 6.68 - 6.83 (m, 2H), 5.52 - 5.66 (m, 1H), 2.84 - 3.00 (m, 1H), 2.71 - 2.82 (m, 1H), 2.17 (br. s., 2H), 1.84 (br. s, 2H).

[0228] Example S1-4. Synthesis of N-(1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (compound 1-4).

[0229] [ka] Step 1: Synthesis of 1-(2-chloro-6-fluorophenyl)ethan-1-ol. To a stirred solution of 1-(2-chloro-6-fluorophenyl)ethan-1-one (1 gm, 5.8 mmol, 1.0 equiv.) in methanol (5 mL), NaBH4 (465 mg, 12.3 mmol, 2 equiv.) was added portionwise at 0 °C and stirred for 10 minutes. The reaction mixture was allowed to stir at room temperature for 1 hour. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (50 mL × 3). The combined organic extracts were washed with water (50 mL × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 1-(2-chloro-6-fluorophenyl)ethan-1-ol (1 gm as a colorless liquid).

[0230] Step 2: Synthesis of 1-(1-(2-chloro-6-fluorophenyl)ethyl)-4-nitro-1H-pyrazole. To a stirred solution of PPh3 (903 mg, 3.44 mmol, 1.5 equiv) and DIAD (0.669 ml, 3.44 mmol, 1.0 equiv) in THF (2 mL), 4-nitro-1H-pyrazole (260 mg, 2.29 mmol, 1 equiv) was added, followed by 1-(2-chloro-6-fluorophenyl)ethan-1-ol (400 mg, 2.29 mmol, 1.0 equiv). The resulting reaction mixture was stirred at room temperature for 1 hour. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the mixture was diluted with EtOAc (50 mL) and washed with water (50 mL × 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was further purified by flash column chromatography to give the pure product 1-(1-(2-chloro-6-fluorophenyl)ethyl)-4-nitro-1H-pyrazole (320 mg).

[0231] Step 3: Synthesis of 1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-amine. To a stirred solution of 1-(1-(2-chloro-6-fluorophenyl)ethyl)-4-nitro-1H-pyrazole (200 mg, 0.743 mmol, 1 equiv.) in 10 mL of EtOH / water (1:1), Fe (200 mg, 3.71 mmol, 5 equiv.) and ammonium chloride (208 mg, 3.71 mmol, 5 equiv.) were added and heated at 80° C. for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a Celite pad, and the filtrate was evaporated and extracted twice with DCM / water. The organic layer was collected and evaporated under reduced pressure to give 1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-amine (170 mg). LCMS: 240 [M+H] + .

[0232] Step 4: Synthesis of 1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride. To a stirred solution of 1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-amine (150 mg) in ethanol, HCl in ethanol (1 mL) was added and allowed to stir at room temperature for 1 hour. After 1 hour, the reaction mixture was evaporated and lyophilized to give the product 1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride (155 mg). LCMS: 240 [M+H] + .

[0233] Step 5: Synthesis of N-(1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. To a solution of 5-(furan-2-yl)isoxazole-3-carboxylic acid (50 mg, 0.277 mmol, 1 equiv.) in DMF (1 mL) was added HATU (105.5 mg, 0.277 mmol, 1.0 equiv.) and DIPEA (107.99 mL, 0.831 mmol, 3.0 equiv.). After stirring at room temperature for 15 minutes, a solution of 1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride (77 mg, 0.555 mmol, 1 equiv.) in DMF (1 mL) was added. The reaction mixture was kept under stirring for 24 hours. After completion of the reaction, the mixture was diluted with EtOAc (50 mL) and washed with water (10 mL x 3). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was further purified by trituration with acetone:hexane (8:2) to give the precipitate as N-(1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (30 mg). LCMS: 401 [M+H] + , 1H NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 8.14 (s, 1H), 8.00 (d, J = 1.32 Hz, 1H), 7.64 (s, 1H), 7.35 - 7.48 (m, 2H), 7.19 - 7.33 (m, 2H), 7.14 (s, 1H), 6.77 (dd, J = 1.75, 3.51 Hz, 1H), 6.02 (q, J = 7.31 Hz, 1H), 1.92 (d, J = 7.45 Hz, 3H).

[0234] Example S1-5. Synthesis of N-(1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (compound 1-5).

[0235] [ka] Step 1: Synthesis of 1-(2,4-difluorophenyl)ethan-1-ol. To a stirred solution of 1-(2,4-difluorophenyl)ethan-1-one (1 gm, 6.4 mmol, 1.0 equiv.) in methanol (5 mL), NaBH4 (465 mg, 12.3 mmol, 2 equiv.) was added portionwise at 0 °C and stirred for 10 minutes. The reaction mixture was allowed to stir at room temperature for 1 hour. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (50 mL × 3). The combined organic extracts were washed with water (50 mL × 2), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 1-(2,4-difluorophenyl)ethan-1-ol (1 gm as a colorless liquid). 1 H NMR (400 MHz, DMSO-d6): δ 7.45 - 7.61 (m, 1H), 7.00 - 7.20 (m, 2H), 5.33 (d, J = 4.38 Hz, 1H), 4.87 - 5.00 (m, 1H), 1.31 (d, J = 6.58 Hz, 3H).

[0236] Step 2: Synthesis of 1-(1-(2,4-difluorophenyl)ethyl)-4-nitro-1H-pyrazole. To a stirred solution of PPh3 (678 mg, 2.53 mmol, 1 equiv.) and DIAD (0.511 ml, 2.53 mmol, 1.0 equiv.) in THF (2 mL), 4-nitro-1H-pyrazole (286 mg, 2.53 mmol, 1 equiv.) was added, followed by 1-(2,4-difluorophenyl)ethan-1-ol (400 mg, 2.53 mmol, 1.0 equiv.). The resulting reaction mixture was stirred at room temperature for 1 h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the mixture was diluted with EtOAc (50 mL) and washed with water (50 mL × 3), and the organic layer was dried over NaSO and concentrated under reduced pressure to give the crude product, which was further purified by flash column chromatography to give the pure product 1-(1-(2,4-difluorophenyl)ethyl)-4-nitro-1H-pyrazole (170 mg). 1 H NMR (400 MHz, DMSO-d6): δ 9.10 (s, 1H), 8.30 (s, 1H), 7.51 (dd, J = 2.63, 8.77 Hz, 1H), 7.42 (dd, J = 6.14, 8.77 Hz, 1H), 7.26 (dt, J = 2.41, 8.44 Hz, 1H), 6.00 (q, J = 6.87 Hz, 1H), 1.83 (d, J = 7.02 Hz, 3H).

[0237] Step 3: Synthesis of 1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-amine. To a stirred solution of 1-(1-(2,4-difluorophenyl)ethyl)-4-nitro-1H-pyrazole (100 mg, 0.395 mmol, 1 equiv.) in 10 mL of EtOH / water (5:5), Fe (106 mg, 1.976 mmol, 5 equiv.) and ammonium chloride (111 mg, 1.976 mmol, 5 equiv.) were added and heated at 80° C. for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the filtrate was evaporated and extracted twice with DCM / water. The organic layer was collected and evaporated under reduced pressure to give 1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-amine (89 mg). LCMS: 224 [M+H] + .

[0238] Step 4: Synthesis of 1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride. To a stirred solution of 1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-amine (89 mg) in ethanol, HCl in ethanol (1 mL) was added and allowed to stir at room temperature for 1 hour. After completion of the reaction, the reaction mixture was evaporated and lyophilized to give the product 1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride (60 mg). LCMS: 224 [M+H] + .

[0239] Step 5: Synthesis of N-(1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. To a solution of 5-(furan-2-yl)isoxazole-3-carboxylic acid (31.09 mg, 0.171 mmol, 1 equiv.) in DMF (1 mL) was added HATU (65.2 mg, 0.171 mmol, 1.0 equiv.) and DIPEA (0.089 mL, 0.515 mmol, 3.0 equiv.). After stirring at room temperature for 15 minutes, a solution of 1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride (50 mg, 0.171 mmol, 1 equiv.) in DMF (1 mL) was added dropwise. The reaction mixture was kept under stirring for 24 hours. After completion of the reaction, the mixture was diluted with EtOAc (50 mL) and washed with water (10 mL×3), the organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the crude product, which was further purified by trituration with acetone-hexane (8:2) ml to give the precipitate as N-(1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (30 mg). LCMS: 385 [M+H] + , 1 H NMR (400 MHz, DMSO-d6): δ 11.02 (s, 1H), 8.14 (s, 1H), 8.00 (d, J = 0.88 Hz, 1H), 7.69 (s, 1H), 7.22 - 7.38 (m, 3H), 7.14 (s, 1H), 7.03 - 7.10 (m, 1H), 6.77 (dd, J = 1.75, 3.51 Hz, 1H), 5.85 (q, J = 7.02 Hz, 1H), 1.80 (d, J = 7.02 Hz, 3H).

[0240] Example S1-6. Synthesis of N-(1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (compound 1-6).

[0241] [ka] Step 1: Synthesis of 1-(2-chloro-4-fluorophenyl)ethan-1-ol. To a stirred solution of 1-(2-chloro-4-fluorophenyl)ethan-1-one (0.5 gm, 3.205 mmol, 1.0 equiv.) in methanol (5 mL), NaBH (183 mg, 4.807 mmol, 1.5 equiv.) was added portionwise at 0° C. and stirred for 10 minutes. The reaction mixture was allowed to stir at room temperature for 1 hour. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water and extracted with ethyl acetate (50 mL×3). The combined organic extracts were washed with water (50 mL×2), dried over anhydrous NaSO, and concentrated under reduced pressure to give 1-(2-chloro-4-fluorophenyl)ethan-1-ol (0.4 gm as a colorless liquid). 1 H NMR (400 MHz, DMSO-d6): δ 7.43 - 7.64 (m, 1H), 6.97 - 7.19 (m, 2H), 5.33 (d, J = 4.38 Hz, 1H), 4.84 - 5.00 (m, 1H), 1.31 (d, J = 6.58 Hz, 3H).

[0242] Step 2: Synthesis of 1-(1-(2-chloro-4-fluorophenyl)ethyl)-4-nitro-1H-pyrazole. To a stirred solution of PPh3 (611 mg, 2.28 mmol, 1 equiv.) and DIAD (0.460 mg, 2.29 mmol, 1.0 equiv.) in THF (2 mL), 4-nitro-1H-pyrazole (260 mg, 2.29 mmol, 1 equiv.) was added, followed by 1-(2-chloro-4-fluorophenyl)ethan-1-ol (400 mg, 2.29 mmol, 1.0 equiv.). The resulting reaction mixture was stirred at room temperature for 1 h. Product formation was confirmed by TLC and LCMS. After completion of the reaction, the mixture was diluted with EtOAc (50 mL) and washed with water (50 mL × 3), and the organic layer was dried over NaSO and concentrated under reduced pressure to give the crude product, which was further purified by flash column chromatography to give the pure product 1-(1-(2-chloro-4-fluorophenyl)ethyl)-4-nitro-1H-pyrazole (220 mg).1 H NMR (400 MHz, DMSO-d6): δ 9.10 (s, 1H), 8.30 (s, 1H), 7.51 (dd, J = 2.63, 8.77 Hz, 1H), 7.42 (dd, J = 6.14, 8.77 Hz, 1H), 7.26 (dt, J = 2.41, 8.44 Hz, 1H), 6.00 (q, J = 6.87 Hz, 1H), 1.83 (d, J = 7.02 Hz, 3H).

[0243] Step 3: Synthesis of 1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazol-4-amine. To a stirred solution of 1-(1-(2-chloro-4-fluorophenyl)ethyl)-4-nitro-1H-pyrazole (100 mg, 0.395 mmol, 1 equiv.) in 10 mL of EtOH / water (1:1), Fe (107 mg, 1.97 mmol, 5 equiv.) and ammonium chloride (111 mg, 1.976 mmol, 5 equiv.) were added and heated at 80° C. for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a Celite pad, and the filtrate was evaporated and extracted twice with DCM / water. The organic layer was collected and evaporated under reduced pressure to give 1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazol-4-amine (89 mg). 1 H NMR (400 MHz, DMSO-d6): δ 7.15 - 7.24 (m, 1H), 6.97 - 7.15 (m, 2H), 6.93 (s, 1H), 5.74 (br. s., 1H), 5.59 (m, J = 6.58 Hz, 1H), 3.82 (br. s., 2H), 1.68 (d, J = 7.45 Hz, 3H).

[0244] Step 4: Synthesis of 1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride. To a stirred solution of 1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazol-4-amine (118 mg) in ethanol, HCl in ethanol (2 mL) was added and allowed to stir at room temperature for 1 hour. The reaction mixture was evaporated and lyophilized to give the product 1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride (80 mg). 1 H NMR (400 MHz, DMSO-d6): δ 9.9 (s, 2H), 8.04 (s, 1H), 7.60 (s, 1H), 7.49 (dd, J = 2.63, 8.77 Hz, 1H), 7.18 - 7.41 (m, 2H), 5.95 (q, J = 6.87 Hz, 1H), 1.78 (d, J = 7.02 Hz, 3H).

[0245] Step 5: Synthesis of N-(1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. To a solution of 5-(furan-2-yl)isoxazole-3-carboxylic acid (32.72 mg, 0.181 mmol, 1 equiv.) in DMF (1 mL) was added HATU (69.72 mg, 0.181 mmol, 1.0 equiv.) and DIPEA (0.094 mL, 0.54 mmol, 3.0 equiv.). After stirring at room temperature for 15 minutes, a solution of 1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazol-4-amine hydrochloride (50 mg, 0.181 mmol, 1 equiv.) in DMF (1 mL) was added. The reaction mixture was kept under stirring for 24 hours. After completion of the reaction, the mixture was diluted with EtOAc (50 mL) and washed with water (10 mL × 3), and the organic layer was dried over NaSO and concentrated under reduced pressure to give the crude product, which was further purified by trituration with acetone-hexane (8:2) ml to give the precipitate as N-(1-(1-(2-chloro-4-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (30 mg). LCMS: 401 [M+H] + , 1 H NMR (400 MHz, DMSO-d6): δ 11.04 (s, 1H), 8.14 (s, 1H), 8.00 (d, J = 1.75 Hz, 1H), 7.71 (s, 1H), 7.46 - 7.55 (m, 1H), 7.19 - 7.30 (m, 3H), 7.14 (s, 1H), 6.77 (dd, J = 1.75, 3.51 Hz, 1H), 5.91 (q, J = 6.87 Hz, 1H), 1.79 (d, J = 7.02 Hz, 3H).

[0246] Example S1-7. Synthesis of N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(pyrazin-2-yl)isoxazole-5-carboxamide (compound 1-11).

[0247] [ka] Step 1: Synthesis of N'-hydroxypyrazine-2-carboximidamide. To a mixture of pyrazine-2-carbonitrile (1 gm, 9.5 mmol, and 1 eq.) was added NH2OH.HCl (1.32 gm, 0.018 mol, 2 eq.) in 1 ml of ethanol:water (10:10), and Na2CO3 (2 gm, 0.018 mol, 2 eq.) was added. The reaction mixture was refluxed for 16 hours. The reaction mixture was cooled to room temperature. The resulting suspension was filtered. The resulting precipitate was confirmed to be our product, N'-hydroxypyrazine-2-carboximidamide (1.1 gm, white precipitate). 1 H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.06 (d, J = 0.88 Hz, 1H), 8.63 (q, J = 2.63 Hz, 2H), 5.95 (br. s., 2H).

[0248] Step 2: Synthesis of N-hydroxypyrazine-2-carbimidoyl chloride. To a solution of N'-hydroxypyrazine-2-carbimidoamide (200 mg, 1.449 mmol, and 1 equiv.) in HO (5 ml) at 0 °C, NaCl (256.34 mg, 4.34 mmol, and 3 equiv.), 0.1 N HCl (0.4 ml), and acetic acid (1 ml) were added. The reaction mixture was stirred until clear. NaNO (100 mg, 1.449 mmol, and 1 equiv.) was added to the reaction mixture, and stirring was continued at 0 °C for 30 min. The resulting suspension was filtered. The resulting precipitate was confirmed to be our product, N-hydroxypyrazine-2-carbimidoyl chloride (180 mg, white precipitate). 1 H NMR (400 MHz, DMSO-d6) δ13.04 (s, 1H), 9.09 (s, 1H), 8.70 - 8.78 (m, 2H).

[0249] Step 3: Synthesis of ethyl 3-(pyrazin-2-yl)isoxazole-5-carboxylate. To a mixture of N-hydroxypyrazine-2-carbimidoyl chloride (100 mg, 0.632 mmol, 1 equiv.) and ethyl propionate (124.05 mg, 1.265 mmol, 2 equiv.) in DCM (20 mL) at room temperature was added a solution of KCO (218.3 mg, 2.5 mmol, 2 equiv.) in DCM (20 mL) in portions over 60 minutes. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness and worked up by adding water (10 mL). Extraction with ethyl acetate (2 × 25 mL × 2) was performed, and the resulting mixture was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane to give ethyl 3-(pyrazin-2-yl)isoxazole-5-carboxylate as a white solid (80 mg). LCMS: 220 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ 9.27 - 9.39 (m, 1H), 8.76 - 8.92 (m, 2H), 7.82 (s, 1H), 4.42 (q, J = 7.02 Hz, 2H), 1.36 (t, J = 7.24 Hz, H 3H).

[0250] Step 4: Synthesis of 3-(pyrazin-2-yl)isoxazole-5-carboxylic acid. To a solution of ethyl 3-(pyrazin-2-yl)isoxazole-5-carboxylate (60 mg, 0.272 mmol, 1 equiv.) in THF (2 mL) and water (2 mL), lithium hydroxide (13.05 mg, 0.326 mmol, 1.2 equiv.) was slowly added. The resulting mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to give the crude product, which was acidified with 1N HCl, and the resulting suspension was lyophilized. The resulting crude product was triturated with ether. The resulting precipitate (ppt.) 3-(pyrazin-2-yl)isoxazole-5-carboxylic acid was our product (52 mg, off-white solid). LCMS: 192 [M+H] + .

[0251] Step 5: Synthesis of N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(pyrazin-2-yl)isoxazole-5-carboxamide. To a solution of 3-(pyrazin-2-yl)isoxazole-5-carboxylic acid (50 mg, 0.2613 mmol, 1 equiv.) in DMF (2 mL) was added HATU (100.2 mg, 0.261 mmol, 1 equiv.). The mixture was treated dropwise with DIPEA (0.183 mL, 0.783 mmol, 3 equiv.). After stirring at room temperature for 15 minutes, the mixture was treated dropwise with a solution of 1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-amine (84.56 mg, 0.261 mmol, 1 equiv.) in DMF (1 mL). The reaction mixture was kept under stirring for 24 hours. The reaction mixture was diluted with water (50 mL). The resulting precipitate was filtered off. The crude material obtained was purified by flash silica gel chromatography using a mixture of ethyl acetate in hexane and trituration with DCM:hexane (2:8) to give N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(pyrazin-2-yl)isoxazole-5-carboxamide (40 mg). LCMS: 497 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 9.32 (s, 1H), 8.85 (d, J = 7.02 Hz, 2H), 8.21 (s, 1H), 8.02 - 8.12 (m, 2H), 7.74 - 7.81 (m, 3H), 5.95 (m, J = 7.02 Hz, 1H), 1.88 (d, J = 6.58 Hz, 3H).

[0252] Example S1-8. Synthesis of 5-(pyrazin-2-yl)-N-(1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide (compound 1-12).

[0253] [ka] Step 1: Synthesis of 5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol. To a stirred solution of 5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (300 mg, 1.5 mmol, 1 equiv.) in 5 mL of MeOH, NABH4 (88.87 mg, 2.25 mmol, 1.5 equiv.) was added portionwise and allowed to stir at room temperature for 1 hour. The reaction mixture was concentrated and extracted with ethyl acetate and water (2 × 25 mL). The organic layer was collected and evaporated to give 5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.49 - 7.60 (m, 3 H) 5.46 (d, J=6.14 Hz, 1 H) 5.09 (q, J=6.43 Hz, 1 H) 2.98 (ddd, J=16.01, 8.55, 3.51 Hz, 2 H) 2.78 (dt, J=15.90, 8.06 Hz, 1 H) 2.33 - 2.43 (m, 2 H) 1.75 - 1.87 (m, 1 H).

[0254] Step 2: Synthesis of 4-nitro-1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazole. To a stirred solution of PPh3 (583.60 mg, 2.227 mmol, 1.5 equiv) and DIAD (449.95 mg, 2.227 mmol, 1.5 equiv) in THF (10 mL), 5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-ol (300 mg, 1.485 mmol, 1 equiv) and 4-nitro-1H-pyrazole (167.82 mg, 1.485 mmol, 1 equiv) were added and allowed to stir at room temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and water (2×25 mL), the organic layer was separated and evaporated under reduced pressure to give the crude product, which was further purified by combi-flash chromatography to give 4-nitro-1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazole. LCMS: 297 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.11 (s, 1 H) 8.49 (s, 1 H) 7.68 - 7.74 (m, 2 H) 7.50 (dd, J=5.04, 1.97 Hz, 3 H) 7.38 - 7.41 (m, 1 H).

[0255] Step 3: Synthesis of 1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine. To a stirred solution of 4-nitro-1-(2,2,2-trifluoro-1-phenylethyl)-1H-pyrazole (200 mg, 0.738 mmol, 1 equiv.) in 10 mL of EtOH / water (1:1), Fe (202.95 mg, 3.69 mmol, 5 equiv.) and ammonium chloride (195.57 mg, 3.69 mmol, 5 equiv.) were added and heated at 80° C. for 2 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered through a pad of Celite, and the filtrate was evaporated and extracted with DCM / water (2×25 mL). The organic layer was collected and evaporated under reduced pressure to give 1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine. LCMS: 268 [M+H] + .

[0256] Step 4: Synthesis of 5-(pyrazin-2-yl)-N-(1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide. To a stirred solution of 5-(pyrazin-2-yl)isoxazole-3-carboxylic acid (100 mg, 0.524 mmol, 1 equiv.) in DMF (4 mL), HATU (199.12 mg, 0.524 mmol, 1 equiv.) was added and allowed to stir at room temperature for 15 minutes. Then, a stirred solution of 1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-amine (140 mg, 0.524 mmol, 1 equiv.) and DIPEA (202.72 mg, 1.572 mmol, 3 equiv.) was added. The reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was poured into ice-cold water, and the resulting precipitate was filtered off to obtain the crude product, which was purified by Combiflash chromatography to obtain 5-(pyrazin-2-yl)-N-(1-(5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide (30 mg white solid). LCMS: 441 [M+H]+ , 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.12 (s, 1 H) 9.35 (s, 1 H) 8.82 (s, 1 H) 8.85 (s, 1 H) 8.18 (s, 1 H) 7.65 - 7.75 (m, 3 H) 7.55 (d, J=7.89 Hz, 1 H) 7.24 (d, J=7.89 Hz, 1 H) 6.04 (t, J=6.58 Hz, 1 H) 3.20 (d, J=4.82 Hz, 2 H) 3.03 (d, J=8.33 Hz, 2 H).

[0257] Example S1-9. Synthesis of N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide (compound 1-13).

[0258] [ka] Step 1: Synthesis of N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide. To a stirred solution of 5-(thiophen-2-yl)isoxazole-3-carboxylic acid (50 mg, 0.256 mmol, 1.0 equiv.) in DMF (2 mL), HATU (97 mg, 0.256 mmol, 1.0 equiv.) was added and stirred at room temperature for 15 minutes. 1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-amine (65 mg, 0.256 mmol, 1.0 equiv.) was added to the reaction mixture, followed by DIPEA (0.13 mL, 0.769 mmol, 3.0 equiv.), and again stirred at room temperature for 1 hour. The reaction progress was analyzed by TLC and LCMS. After completion of the reaction, the RM was poured into ice-cold water, filtered, and purified using flash chromatography to give N-(1-(1-(2,6-dichlorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide. LCMS mass [M+1]: 433.3, 1H NMR (400 MHz, DMSO-d6) δ ppm 10.99 (s, 1 H) 8.11 (s, 1 H) 7.83 (s,1H) 7.90 (s, 1 H) 7.66 (s, 1 H) 7.38 (d, J=8.33 Hz, 2 H) 7.17 (s,1H) 7.30 (s, 2 H) 6.17 (d, J=7.02 Hz, 1 H) 1.96 (d, J=7.45 Hz, 3 H).

[0259] Example S1-10. Synthesis of N-(1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (Compound 1-14 and Compound 1-15).

[0260] [ka] The racemic mixture of N-(1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (30 mg) was purified by chiral HPLC to give N-(1-(1-(2-chloro-6-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide as the first eluting isomer (compound 1-14) and the second eluting isomer (compound 1-15). The isomers were separated by chiral SFC (Daicel Chiralpak-IA, 250 × 20 mm, total volume). An isocratic program was performed with analytical-grade liquid carbon dioxide and HPLC-grade isopropanol, total flow rate: 56 g / min, cosolvent percentage: 20%. Compound 1-14: Yield = 4 mg; elution time = 9.01 min. Compound 1-15: Yield = 4 mg; elution time = 17.68 min. Compound 1-14: LCMS: 401 [M+1]; 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (S,1H), 8.14 (S, 1H), 8.01 (S, 1H), 7.64 (S, 1H), 7.39 (m, 2H), 7.29 (m, J = 3.51 Hz, 2H), 7.14 (5, 1H), 6.78 @5.,1H), 6.02 (m, 1H), 1.92 (d, J = 6.58 Hz, 3H). Compound 1-15: LCMS: 401 [M+H] + ; 1 H NMR (400 HZ, DMSO-d6) m 11.01 (5, 1H), 8.14 (5, 1H), 8.00 (s, 1H), 7.64 (s, 1H), 7.36 -7.44 (m, 2H), 7.20 -7.30 (m, 2H), 7.14 (5, 1H), 6.77 (m, 1H), 6.04 (m, 1H), 1.92 (d, J = 6.14 Hz, 3H).

[0261] Example S1-11. Synthesis of N-(1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (Compound 1-16 and Compound 1-17).

[0262] [ka] The racemic mixture of N-(1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (30 mg) was purified by chiral HPLC to give N-(1-(1-(2,4-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide as the first eluting isomer (compound 1-16) and the second eluting isomer (compound 1-17). The enantiomers were separated by chiral SFC (Daicel Chiralpak-IA, 250 × 20 mm, total volume). An isocratic program with analytical-grade liquid carbon dioxide and HPLC-grade methanol was used, with a total flow rate of 51 g / min and a cosolvent percentage of 15%. Compound 1-16: Yield = 2 mg; Elution time = 6.2 min. Compound 1-17: Yield = 4 mg; Elution time = 7.5 min. Compound 1-16: LCMS: 385 [M+H]; 1 H NMR (400 MHz, DMSO-d6) δ, 11.01 (s, 1H), 8.14 (s, IH), 8.00 (s, 1H), 7.69 (s, IH), 7.22 - 7.34 (m, 3H), 7.14(s, 1H), 7.08(m, 1H), 6.77(m, 1H), 5.85 (m, J = 7.45 Hz, 1H), 1.79 (d, J = 7.02 Hz, 3H). Compound 1-17: LCMS: 385 [M+1], 1 H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.13 (s, 1H), 8.01(s, 1H), 7.68 (s, 1H), 7.23 -7.35 (m, 3H), 7.15 (s, 1H), 7.06 (m,1H), 6.78 (m, 1H), 5.84 (m, J = 7.45 Hz,1H), 1.78 (d, 3H).

[0263] Example S1-12. Synthesis of N-(1-(1-(2,6-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide (Compounds 1-18 and 1-19)

[0264] [ka] The racemic mixture of N-(1-(1-(2,6-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide (185 mg) was purified by chiral HPLC to give N-(1-(1-(2,6-difluorophenyl)ethyl)-1H-pyrazol-4-yl)-5-(thiophen-2-yl)isoxazole-3-carboxamide as the first eluting isomer (compound 1-18) and the second eluting isomer (compound 1-19). The isomers were separated by chiral SFC (Daicel Chiralpak®-IA, 250 × 20 mm, 5 μm). An isocratic program with analytical-grade liquid carbon dioxide and HPLC-grade methanol was used, with a total flow rate of 56 g / min and a cosolvent percentage of 25%. Compound 1-18: Yield = 50 mg; Elution time = 6.3 min. Compound 1-19: Yield = 50 mg; Elution time = 9.3 min. LCMS mass [M+1]: 401.40; 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.14 (s, 1H), 8.00 (d, J = 1.32 Hz, 1H), 7.64 (s, 1H), 7.35 - 7.45 (m, 2H), 7.28 (d, J = 3.51 Hz, 1H), 7.19 - 7.26 (m, 1H), 7.14 (s, 1H), 6.77 (dd, J = 1.75, 3.51 Hz, 1H), 5.98 - 6.06 (m, 1H), 1.92 (d, J = 6.58 Hz, 3H).

[0265] Example S1-13. Synthesis of 5-(furan-2-yl)-N-(1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide (Compounds 1-20 and 1-21)

[0266] [ka] Step 1: Synthesis of 1-(2,4,6-trifluorophenyl)ethan-1-ol. To a stirred solution of 1-(2,4,6-trifluorophenyl)ethanone (1.00 g, 5.74 mmol, 1.0 equiv.) in ethanol (15 mL), NaBH4 (0.437 g, 11.49 mmol, 2 equiv.) was added portionwise at 0 °C and stirred at room temperature for 2 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was distilled, worked up with 10 mL of water, and extracted with ethyl acetate (2 × 20 mL). The organic layer was separated and evaporated under reduced pressure to give the product, 1-(2,4,6-trifluorophenyl)ethan-1-ol (1.00 g).

[0267] Step 2: Synthesis of 4-nitro-1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazole. To a solution of 1-(2,4,6-trifluorophenyl)ethan-1-ol (1.00 g, 5.68 mmol, 1 eq) and 4-nitro-1H-pyrazole (642 mg, 5.68 mmol, 1.0 eq) in THF (15 ml), TPP (2.23 gm, 8.522 mmol, 1.5 eq) was added and cooled to 0 °C. DIAD (1.72 ml, 8.522 mmol, 1.5 eq) was added dropwise under inert conditions. After the addition, the reaction mixture was stirred at room temperature, and the reaction progress was monitored by TLC and LCMS. After completion of the reaction, workup was done with 10 ml of water and extracted with ethyl acetate (2 x 20 ml) times, the organic layer was separated and evaporated under reduced pressure to give the crude product, which was purified by Combiflash chromatography to give the pure product 4-nitro-1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazole (1.2 g).

[0268] Step 3: Synthesis of 1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazol-4-amine. To a solution of 4-nitro-1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazole (1.2 g, 4.428 mmol, 1 equiv.) in 10 mL of EtOH:HO (1:1) was added NH4Cl (1.195 g, 22.140 mmol, 5 equiv.) and Fe (1.239 g, 22.140 mmol, 5 equiv.). The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was distilled, worked up with 10 mL of water, extracted with ethyl acetate (2 × 20 mL), and the organic layer was collected and concentrated to give the product 1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazol-4-amine (920 mg).

[0269] Step 4: Synthesis of 5-(furan-2-yl)-N-(1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide. To a solution of 1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazol-4-amine (900 mg, 5.027 mmol, 1 equiv.) in DMF (10 ml), HATU (1.91 g, 5.027 mmol, 1 equiv.) and DIPEA (2.62 ml, 15.08 mmol, 3 equiv.) were added and stirred for 5 minutes. 5-(furan-2-yl)isoxazole-3-carboxylic acid (1.21 g, 5.027 mmol, 1 equiv.) was added and the reaction mixture was stirred at room temperature. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction was worked up with cold water (30 ml) and extracted with ethyl acetate (2×50 mL), the organic layer was collected, dried over sodium sulfate and concentrated to give the crude product, which was purified by Combiflash chromatography using hexane:ethyl acetate to give the product 5-(furan-2-yl)-N-(1-(1-(2,4,6-trifluorophenyl)ethyl)-1H-pyrazol-4-yl)isoxazole-3-carboxamide (350 mg). LCMS: 403 [M+H].

[0270] Example S-14. Synthesis of N-(1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (Compound 1-22)

[0271] [ka] Step 1: Synthesis of 1-(2,6-dichlorophenyl)ethan-1-ol. To a stirred solution of 1-(2,6-dichlorophenyl)ethan-1-one (1.00 g, 5.29 mmol, 1 equiv.) in ethanol (10 ml) at 0 °C, NaBH4 (0.391 g, 10.58 mmol, 2 equiv.) was added. The resulting reaction mixture was stirred at room temperature for 2 hours, and the reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with 3 ml of water, and all the ethanol was distilled off. The reaction mixture was extracted with ethyl acetate (100 ml × 2) and water (100 mL). The organic layer was separated and evaporated under reduced pressure to give the crude product 1-(2,6-dichlorophenyl)ethan-1-ol (1.01 g). LCMS: 191 [M+H]

[0272] Step 2: Synthesis of 1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-4-nitro-1H-pyrazole. To a stirred solution of 1-(2,6-dichlorophenyl)ethan-1-ol (1.00 g, 5.23 mmol, 1 equiv.), 3-methyl-4-nitro-1H-pyrazole (0.700 g, 5.23 mmol, 1 equiv.), and TPP (2.05 g, 7.85 mmol, 1.5 equiv.) in THF (10 ml), DIAD (1.6 ml, 7.85 mmol, 1.5 equiv.) was added dropwise at 0° C. and allowed to stir at room temperature for 4 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and water (2×500 mL). The organic layer was separated and evaporated under reduced pressure to give the crude product, which was further purified by Combiflash chromatography to give 1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-4-nitro-1H-pyrazole (1.32 g). LCMS: 299.9 [M+H]

[0273] Step 3: Synthesis of 1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-1H-pyrazol-4-amine. To a solution of 1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-4-nitro-1H-pyrazole (1.0 g, 3.344 mmol, 1 equiv.) in ethenol:water (1:1, 10 mL), NHCl (0.903 g, 16.722 mmol, 5 equiv.) and Fe (0.936 g, 16.722 mmol, 5 equiv.) were added, and the resulting reaction mixture was stirred at 80 °C for 4 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the RM was filtered through a celite bed, the ethanol was evaporated, and the RM was extracted with ethyl acetate and water (2 × 50 mL). The organic layer was collected and concentrated to give the crude product 1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-1H-pyrazol-4-amine (0.560 g). LCMS: 270.02 [M+H].

[0274] Step 4: Synthesis of N-(1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. To a stirred solution of 5-(furan-2-yl)isoxazole-3-carboxylic acid (0.365 g, 2.044 mmol, 1 eq.) and HATU (0.776 gm, 2.044 mmol, 1 eq.) in DMF (5 mL) for 5 minutes, DIPEA (1 ml, 6.133 mmol, 3 eq.) and 1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-1H-pyrazol-4-amine (0.550 g, 2.044 mmol, 1 eq.) were added and the resulting reaction mixture was stirred at room temperature for 4 hours, the reaction progress was monitored by TLC and LCMS, after completion of the reaction the reaction mixture was extracted with ethyl acetate and water (2×25 mL). The organic layer was collected and concentrated to give the crude product, which was purified by Combiflash chromatography to give N-(1-(1-(2,6-dichlorophenyl)ethyl)-5-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (80 mg). LCMS: 431.0 [M+H], 1 H NMR (400MHz, DMSO-d6) 10.19 (s, 1H), 7.99 (s, 1 H), 7.64 (s,1 H), 7.49 -7.13 (s, 5H), 6.76 (d, J = 3.5 Hz, 1 H), 6.26 (m, 1 H), 1.92 (d, J = 7.0 Hz, 3 H), 1.80 (s, 3 H).

[0275] Example S1-15. Synthesis of N-(1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (Compound 1-23 and Compound 1-24).

[0276] [ka] Step 1: Synthesis of 1-(2,6-dichlorophenyl)ethan-1-ol. To a stirred solution of 1-(2,6-dichlorophenyl)ethan-1-one (1.00 g, 5.29 mmol, 1 equiv.) in ethanol (10 ml) at 0 °C, NaBH4 (0.391 g, 10.58 mmol, 2 equiv.) was added, and the resulting reaction mixture was stirred at room temperature for 2 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, water (3 ml) was added, all ethanol was distilled, and the reaction mixture was extracted with ethyl acetate (100 ml × 2) and water (100 mL). The organic layer was separated and evaporated under reduced pressure to give the crude product 1-(2,6-dichlorophenyl)ethan-1-ol (1.01 g). LCMS: 191 (M+H) +

[0277] Step 2: Synthesis of 1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-4-nitro-1H-pyrazole. To a stirred solution of 1-(2,6-dichlorophenyl)ethan-1-ol (1.00 g, 5.23 mmol, 1 equiv.), 3-methyl-4-nitro-1H-pyrazole (0.700 g, 5.23 mmol, 1 equiv.), and TPP (2.05 g, 7.85 mmol, 1.5 equiv.) in THF (10 ml), DIAD (1.6 ml, 7.85 mmol, 1.5 equiv.) was added dropwise at 0 °C and allowed to stir at room temperature for 4 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was extracted with ethyl acetate (100 ml × 2) and water (100 mL). The organic layer was separated and evaporated under reduced pressure to give the crude product, which was further purified by Combiflash chromatography to give 1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-4-nitro-1H-pyrazole (1.32 g). LCMS: 299.9 [M+H].

[0278] Step 3: Synthesis of 1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-amine. To a solution of 1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-4-nitro-1H-pyrazole (1.0 g, 3344 mmol, 1 equiv.) in ethenol:water (1:1, 10 ml), NHCl (0.903 g, 16.722 mmol, 5 equiv.) and Fe (0.936 g, 16.722 mmol, 5 equiv.) were added, and the resulting reaction mixture was stirred at 80 °C for 4 h. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the RM was filtered through a celite bed, ethanol was evaporated, extracted with ethyl acetate and water (2 x 50 mL), the organic layer was collected and concentrated to give crude product 1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-amine (0.560 g). LCMS: 270.02 [M+H].

[0279] Step 4: Synthesis of N-(1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide. To a stirred solution of 5-(furan-2-yl)isoxazole-3-carboxylic acid (0.332 gm, 1.858 mmol, 1 eq) and HATU (0.7063 gm, 1.858 mmol, 1 eq) in DMF (5 mL) for 5 minutes, DIPEA (1 ml, 5.576 mmol, 3 eq) and 1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-amine (0.500 g, 1.858 mmol, 1 eq) were added and the resulting reaction mixture was stirred at room temperature for 4 hours, the reaction progress was monitored by TLC and LCMS, after completion of the reaction the reaction mixture was extracted with ethyl acetate and water (2×25 mL). The organic layer was collected and concentrated to give the crude product, which was purified by Combiflash chromatography to give N-(1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (200 mg). LCMS: 431.0 [M+H], 1 H NMR (400 MHz, DMSO-d6) 10.28 (s, 1H), 7.91 - 8.14 (m, 2H), 7.43 - 7.51 (m, 2H), 7.37 (d, J = 7.89 Hz, 1H), 7.27 (d, J = 3.51 Hz, 1H), 7.16 (s, 1H), 6.77 (dd, J = 1.75, 3.51 Hz, 1H), 3.33 (s, 6H), 2.12 (s, 3H), 1.92 (d, J = 7.02 Hz, 3H).

[0280] Step 5: Separation of N-(1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide isomers. The racemic mixture of N-(1-(1-(2,6-dichlorophenyl)ethyl)-3-methyl-1H-pyrazol-4-yl)-5-(furan-2-yl)isoxazole-3-carboxamide (90 mg) was purified by chiral HPLC to give the first eluting isomer (compound 1-23; 30 mg) and the second eluting isomer (compound 1-24; 30 mg). Compound 1-23: LCMS: 431 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) 10.28 (s, 1H), 8.05 - 8.01 (d, J = 0.88 Hz, 2H), 7.48 (d, J = 8.33 Hz, 2H), 7.32 - 7.16 (s, 3H), 6.77 (dd, J = Compound 1-24: LCMS: 431 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) 10.28 (s, 1H), 8.05 - 8.01 (d, J = 0.88 Hz, 2H), 7.48 (d, J = 8.33 Hz, 2H), 7.32 - 7.16 (s, 3H), 6.77 (dd, J = 2.19, 3.51 Hz, 1H), 6.02 - 6.17 (m, 1H), 2.04 - 2.15 (m, 3H), 1.92 (d, J = 7.02 Hz, 3H).

[0281] Example S1-16. Synthesis of N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(pyrazin-2-yl)isoxazole-5-carboxamide (Compound 1-25 and Compound 1-26).

[0282] [ka] The racemic mixture of N-(1-(1-(2,4-bis(trifluoromethyl)phenyl)ethyl)-1H-pyrazol-4-yl)-3-(pyrazin-2-yl)isoxazole-5-carboxamide (130 mg) was purified by chiral HPLC to give the first eluting isomer (compound 1-25) and the second eluting isomer (compound 1-26). The enantiomers were separated by chiral SFC (Daicel Chiralpak®-IC, 250 × 21 mm, 5 μm). An isocratic program with analytical-grade liquid carbon dioxide and HPLC-grade methanol was used, with a total flow rate of 56 g / min and a cosolvent percentage of 33%. Compound 1-25: Yield = 29 mg; Elution time = 3.0 min. Compound 1-26: Yield = 32 mg; Elution time = 4.2 min. Compound 1-25: LCMS: 497.11 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.24 (s, 1 H) 9.32 (s, 1 H) 8.75 - 8.94 (m, 2 H) 8.21 (s, 1 H) 8.02 - 8.16 (m, 2 H) 7.70 - 7.86 (m, 3 H) 5.95 (d, J=7.02 Hz, 1 H) 1.88 (d, J=7.02 Hz, 3 H). Compound 1-26: LCMS: 497.11 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.22 (s, 1 H) 9.30 (s, 1 H) 8.73 - 8.94 (m, 2 H) 8.21 (s, 1 H) 8.01 - 8.16 (m, 2 H) 7.74 - 7.86 (m, 3 H) 5.92 (d, J=7.02 Hz, 1 H) 1.84 (d, J=7.02 Hz, 3 H).

[0283] Biological Examples Example B1. ERSE ATF6-Luciferase Assay To understand how exemplary compounds of the present invention modulate the activity of ATF6 in the absence or presence of endoplasmic reticulum (ER) stress, human osteosarcoma (U2-OS)-based TRE-luciferase reporter stable cell lines were generated to determine the regulation of transcription of ATF6 target genes.

[0284] U2-OS cells were obtained from the American Type Culture Collection (ATCC HTB-96, ATCC Manassas, VA) and cultured in growth medium containing Dulbecco's modified Eagle's medium (DMEM) (Cat. No.: SH30023.02, HyClone) supplemented with 10% fetal bovine serum (FBS) (Cat. No.: 16000044, Gibco) and 1% penicillin-streptomycin antibiotic cocktail (Cat. No.: SV30010, Hyclone).

[0285] A stable cell line was generated in U2-OS cells using the Cignal Lenti ATF6 luc reporter (Qiagen #CLS-6031L) (U2-OS ATF6 TRE-luciferase reporter). The lenti ATF6 reporter is a preparation of replication-deficient, VSV-g pseudotyped lentiviral particles that express the firefly luciferase gene under the control of a minimal (m)CMV promoter and tandem repeats of the ATF6 transcription response element (TRE). The number of response elements and intervening sequences between response elements was experimentally optimized to maximize the signal-to-noise ratio.

[0286] Exemplary compounds of the invention and reference compounds were prepared from powder as 10 mM stock solutions in dimethyl sulfoxide (DMSO; Cat. No. #D2650, Sigma Aldrich) and stored at -80°C in the presence of a N2 neutral atmosphere.

[0287] For the primary screen, 40,000 U2-OS ATF6 TRE-luciferase reporter cells were seeded with 100 μL of growth medium in a white 96-well plate (Thermo Scientific Nunc #136101) pre-coated with poly-D-lysine (Cat. No.: P2636, Sigma). The cells were incubated in a humidified chamber for 24 hours.

[0288] To test exemplary compounds in the presence of ER stress, cells were pretreated for 30 minutes with 50 μL of growth medium containing either vehicle (DMSO) or 1 or 10 μM of test compound. After this preincubation, 50 μL of a solution containing 0.2 μM of the ER stress inducer thapsigargin (Tg) was added to the appropriate wells. The Tg solution also contained vehicle or 1 or 10 μM of test compound, as indicated. The final concentration of DMSO in each well was kept at 0.3%. The plate was incubated in a humidified chamber for 8 hours.

[0289] After 8 hours of incubation, the plate was cooled to room temperature for 10 minutes before luciferase assay. Luciferase reaction was performed using a luciferase assay system (Cat. No.: E4550, Promega). Briefly, each well was washed with 100 μl of PBS 1×, and then 20 μl of lysis reagent was added to each well. The plate was shaken for 10 minutes, and then 50 μl of luciferase assay reagent was added to each well. Luminescence was determined in a Synergy 4 microplate reader with a 1-second integration at a gain of 110. All measurements were performed in triplicate.

[0290] The average activity determined from wells containing only the vehicle (DMSO, 0% ATF6 activity) was used as a blank and subtracted from the rest of the measurements. The average activity determined from wells containing only Tg was used as 100% ATF6 activity. The percentage of modulation of exemplary compounds was calculated by normalizing the value to the potential maximum activation by Tg. In this assay, exemplary compounds showing ATF6 activity greater than 100% (positive modulation) indicate activator activity for those molecules, while compounds showing ATF6 activity less than 100% (negative modulation) indicate inhibitory modulation.

[0291] The ATF6 activity of exemplary compounds at 1 and 10 μM in the presence of Tg-induced ER stress, tested in U2-OS ATF6 TRE-luciferase reporter cells, was determined and is shown in Table 2.

[0292] [Table 2]

[0293] To test exemplary compounds in the absence of ER stress, cells were treated for 8 hours with 100 μL of growth medium containing either vehicle (DMSO), 1 or 10 μM of test compound, or 0.1 μM of Tg. The final concentration of DMSO in each well was kept at 0.3%. Plates were incubated in a humidified chamber.

[0294] After 8 hours of incubation, the plates were cooled to room temperature for 10 minutes before the luciferase assay. The luciferase reaction was performed as described above. Luminescence was read in a Synergy 4 microplate reader with a gain of 110 and a 1 second integration. All measurements were performed in triplicate.

[0295] The average activity determined from wells containing vehicle only (DMSO, 0% ATF6 activity) was used as a blank and subtracted from the rest of the measurements. The percentage of modulation for exemplary compounds was calculated by normalizing values ​​to the potential maximal activation by Tg.

[0296] The ATF6 activity of exemplary compounds at 1 and 10 μM was determined in the absence of Tg-induced ER stress in U2-OS ATF6 TRE-luciferase reporter cells and is shown in Table 3.

[0297] [Table 3]

[0298] All references to publications, patents, patent applications, and published patent applications are incorporated herein by reference in their entirety.

[0299] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain minor changes and modifications may be practiced. Accordingly, the specification and examples should not be construed as limiting the scope of the invention.

[0300] SEQUENCE LISTING <110> Altos Labs, Inc. <120> ATF6 MODULATORS AND USES THEREOF <130> PA25-527 <150> US 62 / 913,126 <151> 2019-10-09 <160> 1 <170> FastSEQ for Windows Version 4.0 <210> 1 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Synthetic Construct <400> 1 ccaatcggcg gcggccacg 19

Claims

1. A compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (In the formula, R ｄ is H or C １ -C ６ is alkyl, R １ is C １ -C ６ Alkyl, C ３ -C ８ cycloalkyl, or C １ -C ６ is haloalkyl, L is -CH ２ - or absent, -- is a bond or is absent, R ２ , R ３ , R ４ , R ５ , and R ６ are each independently H, halo, CN, C １ -C ６ Alkyl, or C １ -C ６ haloalkyl, and R ２ , R ３ , R ４ , R ５ , and R ６ At least two of them are halo, CN, C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, and / or R ２ , R ３ , R ４ , R ５ , and R ６ One of the is CN or Or R ２ , R ４ , R ５ , and R ６ are each independently H, halo, CN, C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, -- is a bond, whereby R ３ But, R １ and together with the atom to which they are attached form a 5- or 6-membered carbocyclic ring, which 5- or 6-membered carbocyclic ring is unsubstituted or is substituted with halo, CN, —OH, C １ -C ６ Alkyl, and C １ -C ６ substituted with 1 to 3 groups selected from the group consisting of haloalkyl; A is, 【Chemistry 2】 and R ａ is a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl is unsubstituted or is selected from the group consisting of OH, halo, C １ -C ６ Alkyl and C １ -C ６ substituted with 1 to 4 groups selected from the group consisting of alkoxy; However, A is 【Transformation 3】 and R ａ is 2-furyl or 2-thiofuryl, then at least one of (i.) to (vi.) applies; (i.) L is absent and R １ is C １ -C ６ is alkyl, (ii.) -- is a bond, whereby R ３ But, R １ and together with the atom to which they are attached form a 5- or 6-membered carbocyclic ring, provided that when a 5-membered carbocyclic ring is formed, R ２ , R ４ , R ５ , and R ６ At least one of halo, CN, C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, (iii.) R ２ , R ３ , R ４ , R ５ , and R ６ One of the is CN, (iv.) R ４ and R ５ are each independently Cl, Br, I, CN, or C １ -C ６ Alkyl, or C １ -C ６ is haloalkyl, (v.) R ２ and R ３ are each Cl, (vi.) R ２ , R ３ , R ４ , R ５ , and R ６ At least one of F, Br, I, CN, or C １ -C ６ haloalkyl, and R ａ is 2-thiofuryl, R ７ is H, C １ -C ６ Alkyl or C １ -C ６ is haloalkyl, However, R ｄ is C １ -C ６ When R is alkyl, ７ is H and R ７ is C １ -C ６ When R is alkyl, ｄ is H).

2. R ａ 2. The compound of claim 1, wherein the 5- or 6-membered heteroaryl is selected from the group consisting of 2-furyl, 2-pyridinyl, 2-pyrimidinyl, 4-pyrimidinyl, and 2-pyrazinyl.

3. A is 【Chemistry 4】 and R ａ The compound according to claim 1 or 2, wherein is 2-furyl.

4. A is 【Transformation 5】 and R ａ The compound of claim 1 or 2, wherein is 2-pyridinyl.

5. A is 【Transformation 6】 and R ａ The compound of claim 1 or 2, wherein is 2-pyrimidinyl.

6. A is 【Transformation 7】 and R ａ The compound of claim 1 or 2, wherein is 4-pyrimidinyl.

7. A is 【Transformation 8】 and R ａ The compound of claim 1 or 2, wherein is 2-pyrazinyl.

8. A is 【Chemistry 9】 and R ａ The compound according to claim 1 or 2, wherein is 2-furyl.

9. A is 【Chemistry 10】 and R ａ The compound of claim 1 or 2, wherein is 2-pyridinyl.

10. A is 【Chemistry 11】 and R ａ The compound of claim 1 or 2, wherein is 2-pyrimidinyl.

11. A is 【Chemistry 12】 and R ａ The compound of claim 1 or 2, wherein is 4-pyrimidinyl.

12. A is 【Chemistry 13】 and R ａ The compound of claim 1 or 2, wherein is 2-pyrazinyl.

13. A is 【Chemistry 14】 and R ａ The compound according to claim 1 or 2, wherein is 2-furyl.

14. A is 【Chemistry 15】 and R ａ The compound of claim 1 or 2, wherein is 2-pyridinyl.

15. A is 【Chemistry 16】 and R ａ The compound of claim 1 or 2, wherein is 2-pyrimidinyl.

16. A is 【Chemistry 17】 and R ａ The compound of claim 1 or 2, wherein is 4-pyrimidinyl.

17. A is [Chemistry 18] and R ａ The compound of claim 1 or 2, wherein is 2-pyrazinyl.

18. -- is a bond, whereby R ３ But, R １ and together with the atoms to which they are attached form a five-membered carbocyclic ring.

19. -- is a bond, whereby R ３ But, R １ and together with the atoms to which they are attached form a six-membered carbocyclic ring.

20. A is 【Chemistry 19】 and R ａ is 2-furyl, L is absent, and R １ is C １ -C ６ 4. The compound of claim 1, wherein the aryl group is alkyl.

21. A is 【Chemistry 20】 and R ａ is 2-furyl and -- is a bond, whereby R ３ But, R １ and together with the atom to which they are attached form a 5- or 6-membered carbocyclic ring, provided that when a 5-membered carbocyclic ring is formed, R ２ , R ４ , R ５ , and R ６ At least one of halo, CN, C １ -C ６ Alkyl, or C １ -C ６ 4. The compound of any one of claims 1 to 3, which is haloalkyl.

22. L is absent and R ３ But, R １ and together with the atoms to which they are attached form a 5-membered carbocyclic ring, R ２ , R ４ , R ５ , and R ６ At least one of halo, CN, C １ -C ６ Alkyl, or C １ -C ６ 22. The compound of claim 21 which is haloalkyl.

23. L is absent and R ３ But, R １ and together with the atoms to which they are attached form a 6-membered carbocyclic ring, R ２ , R ４ , R ５ , and R ６ 22. The compound of claim 21, wherein each of is hydrogen. 【Request Item 24】 【Chemistry 21】 【change】 【change】 【change】 【change】 a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

25. 25. A pharmaceutical composition comprising a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. A method for treating a disease or disorder mediated by activating transcription factor 6 (ATF6) in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 25.

27. A method for treating a disease or disorder characterized by activation of ATF6 in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 25.

28. The method of claim 26 or 27, wherein the ATF6 is ATF6α.

29. 29. The method of any one of claims 26 to 28, wherein the disease or disorder is cancer, a neurodegenerative disease, or a vascular disease.

30. 29. The method of any one of claims 26 to 28, wherein the disease or disorder is a viral infection, hereditary cerebellar atrophy and ataxia, or Alzheimer's disease, type 2 diabetes, diabetic nephropathy, myocardial atrophy, heart failure, atherosclerosis, ischemia, ischemic heart disease, or cerebral ischemia.

31. 26. A method of treating cancer in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 25.

32. 26. A method for treating an angiogenesis-associated disease or disorder in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 25.

33. 26. A method for treating a metabolic disorder in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 25.

34. A method for regulating ATF6 in an individual, comprising administering to the individual a compound described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 25.

35. A method for regulating ATF6 in a cell, comprising administering or delivering to the cell a compound described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 25, or a metabolite thereof.

36. A method for activating ATF6 in an individual, comprising administering to the individual a compound described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 25.

37. A method for activating ATF6 in a cell, comprising administering or delivering to the cell a compound described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 25, or a metabolite thereof.

38. A method for inhibiting ATF6 in an individual, comprising administering to the individual a compound described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 25.

39. A method for inhibiting ATF6 in a cell, comprising administering or delivering to the cell a compound described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 25, or a metabolite thereof.

40. Use of a compound described in any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 25, in the manufacture of a pharmaceutical for the prevention and / or treatment of a disorder or disease mediated by ATF6.

41. 25. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use in therapy.

42. 25. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or disorder mediated by activating transcription factor 6 (ATF6) in an individual in need thereof.

43. 25. A compound according to any one of claims 1 to 24 for use in a method for treating a disease or disorder characterized by activation of ATF6 in an individual in need thereof.

44. 44. The compound, or a pharmaceutically acceptable salt thereof, for use according to claim 42 or 43, wherein ATF6 is ATF6α.

45. 45. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 42 to 44, wherein the disease or disorder is cancer, a neurodegenerative disease, or a vascular disease.

46. 45. The compound, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 42 to 44, wherein the disease or disorder is a viral infection, hereditary cerebellar atrophy and ataxia, or Alzheimer's disease, type 2 diabetes, diabetic nephropathy, myocardial atrophy, heart failure, atherosclerosis, ischemia, ischemic heart disease, or cerebral ischemia.

47. 25. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use in a method for treating an angiogenesis-associated disease or disorder in an individual in need thereof.

48. 25. A compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, for use in a method for treating a metabolic disorder in an individual in need thereof.

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